Methods for reducing the risk of strokes by pharmacotherapy to reduce the number and duration of atrial fibrillations

ABSTRACT

Disclosed are methods to treat patients with AFib by monitoring their heart rhythm to determine the presence and/or the number of episodes of long duration AFib, and optionally the extent of AFib burden. Patients who meet threshold requirements are qualified for the treatment of AFib with a dosage of budiodarone. Patient monitoring is continued in order confirm that the patient is and remains responsive to budiodarone therapy including dose adjusting the patient to achieve such therapy. Subsequently, monitoring is continued to confirm that the patient remains responsive. These methods allow for treatment of the AFib and, correspondingly, reduce or delay the risk of stroke and/or congestive heart failure in the treated patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 17/978,835, filed Nov. 1, 2022, which claims the benefit ofU.S. Provisional Application No. 63/334,852, filed Apr. 26, 2022, andU.S. Provisional Application No. 63/297,426, filed Jan. 7, 2022, theentire contents of each of which is incorporated herein by reference.

FIELD

Disclosed are methods and devices for reducing the risk of strokesand/or congestive heart failure in patients diagnosed with paroxysmal orpersistent atrial fibrillation (AFib) by determining whether a patientqualifies for, and then treating the patient with pharmacotherapy whichreduces the number and/or duration of episodes of AFib.

STATE OF THE ART

AFib is a serious medical condition characterized by an abnormal heartrhythm often at accelerated heart rates. Untreated AFib leads to asignificant increase in the risk of strokes, congestive heart failure,and death.

AFib has been categorized into at least three groups. Patients withintermittent episodes of AFib that last no more than 7 days beforereturning to normal, either on its own or with treatment, are defined ashaving paroxysmal AFib. Patients with intermittent episodes of AFib thatlast for more than 7 days before returning to normal are defined ashaving persistent AFib. Finally, patients who are constantlyexperiencing AFib are defined as having permanent AFib.

The underlying irregularity of the heart rhythm in AFib results inaccumulation of blood in the upper chambers of the heart. The longer theblood remains in the upper chambers, the more likely that portion of theblood will coagulate and form clots. Once these clots leave the heart,they can enter the brain and cause strokes. In some cases, the bloodclots cause transient ischemic attacks (TIAs) in the patient. Such TIAscan cause the patient to feel weakness on one side of the body, slurredspeech, or impaired vision which is transitory in nature. In othercases, the blood clots cause debilitating strokes that can result inanything from a loss of functionality, such as speech or mobility, to acompletely comatose state, or death.

In addition, AFib has been associated with not only an increased risk ofstroke but also an increased risk of congestive heart failure—a seriousdebilitating condition that in the long term is terminal. The risk ofstroke and/or congestive heart failure in patients with AFib issignificantly higher than in those with a normal heart rhythm, and therisk increases with the duration and number of each episode of AFib(collectively the AFib burden). For example, the recent ENGAGE clinicaltrial evaluated the risk of stroke for patients, which is set forth inTable 1 below:

TABLE 1 normal heart rhythms ~1% per year % increase over normalparoxysmal heart rhythms ~1.49% per year 49% persistent heart rhythms~1.83% per year 83% permanent heart rhythms ~1.95% per year 95%

Recent studies have shown that an increase in the risk of stroke and/orcongestive heart failure is independent of whether the patient issymptomatic or asymptomatic for AFib. See, for example, Flaker, et al.,Asymptomatic Atrial Fibrillation: Demographic Features and PrognosticInformation from the Atrial Fibrillation Follow-Up Investigation ofRhythmic Management (AFFIRM) Study, American Heart Journal, April 2005,pages 657-663 which is incorporated herein by reference in its entirety.Stated differently, recognition by the patient of periodic AFib episodesdoes not mean that the risk of stroke or congestive heart failure hasbeen reduced or removed.

In addition, there is a recognition that long duration episodes of AFib(i.e., AFib episodes that last 1 hour or more) carry an increased riskof stroke, which increases as the duration of these episodes increases.The longer the duration of the episode, the higher the risk of a stroke.Accordingly, AFib episodes greater than one hour are designated as “longduration” episodes. Still further, such long duration episodes aredivided into two subsets: “medium-long duration” episodes, which arefrom about 1 hour to about 24 hours or less in duration, and“longer-duration” episodes which are longer than about 24 hours induration, but not permanent AFib. However, not all patients sufferingfrom paroxysmal AFib or persistent AFib will evidence long durationAFib. Indeed, the AFib burden is related to, but distinct from,medium-long or longer-duration AFib. For example, patients with a lowAFib burden may experience episodes of long duration AFib, albeit on aninfrequent basis. Likewise, patients with a higher AFib burden mayexperience multiple short duration episodes of AFib, but little or nolong duration episodes. The ability to distinguish between AFib burdenand long duration AFib is essential to address the risk of stroke,congestive heart failure, and the like. This is particularly importantto an attending clinician who must evaluate the efficacy ofpharmacotherapy designed to reduce the number and duration of AFibepisodes.

Several drugs are designed to treat AFib, including beta blockers andcalcium channel blockers. Many of these drugs are designed to controlheart rates rather than controlling heart rhythm. However, the risk ofstroke is related to extended episodes of AFib, and not the underlyingheart rate. Recently, budiodarone (disclosed in U.S. Pat. No. 9,549,912,which is incorporated by reference in its entirety) has been shown tocontrol heart rhythm and significantly reduce episodes of long durationAFib. However, because not all patients with AFib evidence episodes oflong duration AFib, administration of such a heart rhythm drug to justany patient who experiences AFib is not recommended. Even for thosepatients with medium-long duration and/or longer-duration episodes ofAFib who are being treated with budiodarone, the extent of reduction inAFib episodes is dose-dependent and variable from patient to patient dueto the age, sex, weight, extent of disease progression and other factorsknown in the art. In addition, as with other pharmacotherapy treatments,there will invariably be patients who do not respond.

While there are many wearables available that can diagnose the presenceof AFib in a patient including watches, Holter monitors, patches, andthe like, the ability to simply diagnose is different from the abilityto continuously assess the presence of long duration AFib in patientssuffering from paroxysmal or persistent AFib. Continuous monitoring of apatient's heart rhythm is now possible with wearables such as patchesand/or devices. The latter includes wireless transmission devices (suchas MCOT (mobile cardiac outpatient telemetry) sold by PhillipsBioSciences, Best, Netherlands) that allow for seamless collection of apatient's heart rhythm data. To date, such devices have been primarilyused in naïve patients suspected of having AFib, and as such, haveprimarily been used for diagnosis. Currently, there are no exampleswhere these devices should or could be used in combination withpharmacotherapy to assess responsive and non-responsive patients todrugs that are designed to reduce long duration episodes of AFib. Thiswould include enabling the clinician to monitor the disease progressionand/or regression in a treated patient and dose-adjusting the amount ofdrug to achieve an initial therapeutic result or dose-adjusting thepatient to regain or maintain a therapeutic result at the lowestpossible dose.

As such, clinicians are typically left with only minimal short-term dataof up to about 2 weeks or so regarding a patient's heart rhythm overthis span. Such limited data can blind the clinician to conditions wheresporadic episodes of AFib occur infrequently but are of long durationwhich can be easily missed using only short-term data. Moreover, andperhaps more seriously, many diagnostic devices are not compatible withmonitoring and/or pharmacotherapy. This is because the diagnosisrequires short-term monitoring whereas pharmacotherapy requirescontinuous long-term monitoring of the patient by the clinician toassess whether the prescribed drug is effective in reducing both thenumber of long duration episodes of AFib as well as reducing thepatient's AFib burden.

Thus, there exists an ongoing conundrum; how can the clinician considerpharmacotherapy with a drug such as budiodarone to reduce both AFibburden and long duration episodes of AFib if the clinician is unaware ofthe long-term values for either metric in the patient? Moreover, if theclinician does prescribe this drug, how can the clinician know if thedosing of the drug is effectively reducing the episodes of long durationepisodes of AFib? In the absence of such information, the clinician willlikely protect the patient by prescribing a blood thinner such asrivaroxaban (Xarelto®) which reduces clotting arising from AFib.However, the use of such blood thinners comes with a price. For example,the Market Insider reported that the use of Xarelto lead to over 15,000adverse events in 2016 alone. See, for example, Report: More than 15,000Adverse Events Linked to Xarelto in 2016,https://markets.businessinsider.com/news/stocks/report-more-than-15-000-adverse-events-linked-to-xarelto-in-2016-1002203317(last accessed Oct. 28, 2022).

In view of the above, there is an ongoing need to improve the monitoringof patients such that the clinician can accurately quantify the numberand duration of long duration episodes of AFib in a patient as well asthe AFib burden. There is a further need to correlate those patientswith long duration AFib, including medium-long or longer-duration AFib,as being suitable for treatment with budiodarone and potentially createa registry of such patients. Still further, there is a need to allow theclinician to determine, directly or indirectly, whether the dosing ofbudiodarone is effective thereby allowing the clinician to adjust thedosing as appropriate or to remove a non-responsive patient frombudiodarone therapy.

SUMMARY

Disclosed are methods and devices useful in qualifying patients withsymptomatic or asymptomatic paroxysmal or persistent AFib with treatmentwith an antiarrhythmic drug, such as budiodarone. Such treatment isdesigned to reduce or eliminate the risk of stroke or congestive heartfailure in a patient evidencing episodes of long duration AFib as wellas a threshold level of AFib burden. In particular, the methods anddevices described herein allow for continuous or semi-continuousmonitoring of such a patient's heart rhythm to assess the AFib burdenfor such patients as well as the duration of such episodes. This allowsa clinician to evaluate a patient to determine whether that patient somonitored has a requisite number of episodes of long duration AFib aswell as a threshold level of AFib burden. Patients meeting such criteriaare deemed “qualified” candidates for starting therapy with budiodarone.

Patients already ascertained by conventional means, such as a Holtmonitor, as having episodes of long duration AFib and above thresholdlevels of AFib burden are preferably monitored as above before beingplaced on budiodarone to assess a baseline number and duration of theepisodes of long duration AFib as well as AFib burden to determinewhether subsequent pharmacotherapy is efficacious. In any event, allqualified patients placed on budiodarone therapy are maintained onmonitoring after the start of therapy. Such continued monitoring allowsthe clinician to evaluate the efficacy of the drug for that patient. Inessence, the methods disclosed herein provide for pharmacotherapy withbudiodarone as a form of personalized medicine where the severity of thedisease in a qualified patient is matched with an appropriate dose ofbudiodarone that is minimally efficacious for that patient—or if thepatient is a non-responder, the patient is disqualified from budiodaronetherapy. The methods disclosed herein avoid the use of excessive amountsof budiodarone in treating AFib while understanding that some patientsrequire more budiodarone than others to achieve therapy. Still further,the ability to remove a non-responder from therapy represents a newparadigm in treatment by limiting therapy to those patients who areresponders.

In one embodiment, the overall efficacy of budiodarone in a cohort ofpatients can be improved by limiting the continued administration of thedrug to those patients evidencing a therapeutic result. In one instance,qualified patients are those who have been previously identified orconfirmed to meet minimum thresholds. Qualified patients who showefficacy with budiodarone, either initially and/or after doseadjustments, are continued on the therapy whereas those patients wholack such efficacy (non-responders) are removed from the therapy. Giventhe variability of the underlying AFib burden as well as the number oflong duration AFib episodes in a cohort of patients, budiodarone isefficacious in a significant number of patients, but likely not allpatients. Using the methods and devices described herein in combinationwith budiodarone therapy, the clinician is able to ascertain whether agiven patient qualifies for budiodarone therapy and/or whether thattherapy is providing efficacious results, thereby allowing the clinicianthe ability to maintain therapy for only those patients who benefit frombudiodarone treatment and at a minimal dose that is needed to achieveefficacious results.

The above represents a significant advancement in the treatment ofsymptomatic and asymptomatic paroxysmal or persistent AFib in patientswho may or may not have episodes of long duration AFib and/or who may ormay not obtain efficacious results with budiodarone. Such is notpossible by protocols that are limited to diagnosis.

By using the wearables described herein, the clinician can qualify onlythose patients with paroxysmal and/or persistent AFib who evidencethreshold levels of long duration episodes of AFib and/or AFib burdenfor treatment with budiodarone. Still further, the clinician can thenmonitor these patients to assess whether the patient's AFib isresponsive to such treatment or whether dose adjustment of budiodaroneis warranted. Finally, the clinician can also remove non-responsivepatients from such therapy. Such represents a solution to a long feltneed in the art—namely how to control long-duration AFib to reduce therisk of stroke or congestive heart failure.

Optionally, such qualifying patients can be placed on a nationalregistry that enables the clinician to prescribe budiodarone solely tosuch registered patients. Patients who show efficacy with budiodarone,either initially and/or after dose adjustments, are retained on theregistry, whereas patients who lack such efficacy are removed from theregistry.

The devices (wearables) described herein address a critical gap ingenerating the information to allow a clinician to properly evaluate thelong-term heart rhythm of a patient, especially as it relates toassessing the patient's AFib burden and the number and duration of longduration episodes of AFib, before and/or after the start of budiodaronetherapy. Still further, the continued availability of such informationafter initiation of therapy allows the clinician to dose-adjust theamount of budiodarone administered to reach a desired therapeutic resultat a reduced effective dose (e.g., the minimum effective dose). Stillfurther, these methods and/or devices will elicit patient participationthrough self-monitoring, which is a well-accepted way of improvingpatient compliance with their drug regimen. This, in turn, willreinforce the long-term efficacy of any antiarrhythmic drug treatment inreducing or eliminating long-term risks of stroke.

In one embodiment, a wearable is engageable and disengageable by apatient, who may, be diagnosed with paroxysmal AFib or persistent AFib.The wearable may comprise and/or be configured to receive data from atleast one electrode and/or optical sensor that, when the wearable isengaged, continuously or semi-continuously monitors the patient's heartrhythm. The wearable may also, or alternatively, comprise a processingunit (e.g., a processor, a central processing unit (CPU), amicroprocessor, a digital signal processor, a computing device, and thelike) that is configured to collect and optionally evaluate the heartrhythm data to determine the presence of and/or number of long durationepisodes of AFib. The processing unit may also, or alternatively, beconfigured to store the heart rhythm data. The wearable may also, oralternatively, comprise a transmission component (e.g., a transmissiondevice) that is configured to access the data in the processing unit(e.g., wirelessly and/or via circuitry that connects the transmissioncomponent and the processing unit). The transmission component may becapable of initiating a communication directly or indirectly to acomputing device accessible by the patient and/or a clinician and/oranother caregiver of the patient, wherein the communication may providethe heart rhythm data and/or data resulting from evaluating the heartrhythm data.

In another embodiment, a method for monitoring a patient treated forAFib for one or more long duration episodes of AFib may include engagingan engageable and disengageable wearable. The wearable may comprise atleast one electrode or optical sensor that can continuously orsemi-continuously monitor a heart rhythm. The wearable may comprise atransmission device and/or circuitry that connects the at least oneelectrode or optical sensor and the transmission device. The wearablemay also or alternatively, comprise a CPU that can collect the heartrhythm data, evaluate said data for the presence of long durationepisodes of AFib; and store the data. The method may further comprisecommunicating to the patient and/or the patient's caregiver the heartrhythm data, which may enable the caregiver to analyze one or more longduration episodes of AFib.

In another embodiment, a method may be a method for reducing risk of oneor more of: transitioning from paroxysmal AFib to persistent AFib in apatient with paroxysmal AFib; transitioning from persistent AFib topermanent AFib in a patient with persistent AFib; or stroke in a patientwith AFib, wherein the patient is being treated with budiodarone and thetreatment may have reduced and/or inhibited episodes of long durationAFib. The method may include evaluating heart rhythm data collected by awearable engaged by the patient. The wearable may comprise at least oneelectrode or optical sensor that can continuously or semi-continuouslymonitor a heart rhythm. The wearable may comprise a transmission deviceand/or circuitry that connects the at least one electrode or opticalsensor and the transmission device. The wearable may also oralternatively, comprise a CPU that can collect the heart rhythm data,evaluate said data for the presence of long duration episodes of AFib;and store the data. The method may further comprise adjusting the doseof budiodarone to reduce further episodes of long duration AFib (e.g.,as deemed necessary by a clinician), thereby reducing the risk of theone or more of the transitioning from paroxysmal AFib to persistentAFib, the transitioning from persistent AFib to permanent AFib, and/orthe stroke.

In another embodiment, a system may comprise a wearable that collectsheart rhythm data from a patient diagnosed with either paroxysmal AFibor persistent AFib, a CPU that is in communication with the wearable andthat can collect and/or store the data, and a transmission device thatcan communicate with the CPU and that can send the data to one or moredesignated recipients.

In another embodiment, a method may be for reducing the risk of strokeor congestive heart failure in a patient with paroxysmal AFib and/orpersistent AFib and being treated with a pharmaceutical. The method maycomprise obtaining the patient's heart rhythm data from a wearableengaged by the patient, wherein the wearable may comprise at least oneelectrode or optical sensor that can continuously or semi-continuouslymonitor heart rhythm, a transmission device capable of initiatingtransmission of data, circuitry connecting the at least one electrode oroptical sensor and the transmission device, and a CPU configured tocollect and store the heart rhythm data. The method may further compriseevaluating said heart rhythm data to determine the effectiveness of thepharmaceutical by correlating the presence and/or absence of episodes oflong duration AFib to the dose of the pharmaceutical, determiningwhether the dose of the pharmaceutical is effective or ineffective inreducing or eliminating episodes of long duration AFib in the patient;and, if ineffective, increasing the dose one or more time, until saiddose effective, thereby reducing the risk of stroke or congestive heartfailure.

In one embodiment, the wearable is programmable (e.g., by a clinician).In one embodiment, the wearable is programmed to transmit all heartrhythm data and/or only that data of long duration episodes of AFib.

For the purposes of this disclosure, any episode of AFib that has aduration of at least 1 hour is considered a “long duration” episode.However, for clarity, long duration episodes include a subset ofepisodes that are further defined as being of “medium-long duration”.Such medium-long duration episodes range from at least about 1 hour tono more than about 24 hours. Episodes of AFib that range from more thanabout 24 hours but are not permanent are categorized as longer-durationepisodes. These subsets will allow the clinician to better evaluate thebenefits of budiodarone therapy, e.g., when patients with a history oflong-duration episodes of AFib transition to experiencing a greaterpercentage of medium-long duration episodes instead of longer durationepisodes.

In one embodiment, the medium-long duration episodes of AFib range fromabout 1 hour to about 24 hours, and, in another embodiment, suchmedium-long duration episodes of AFib range from at least 5 hours up toabout 24 hours in duration.

In one embodiment, when a first set of collected data is transmitted outof a computing device, such as a central processing unit (CPU), thatdata is discarded from the CPU so that th new data can be collected.

In one embodiment, there is provided a method to assess whether apatient with paroxysmal or persistent AFib qualifies for budiodaronetherapy which method comprises:

-   -   a) selecting a patient afflicted with paroxysmal or persistent        AFib having an unknown AFib burden and/or unknown number of        episodes of long duration AFib over a set period of time;    -   b) fitting said patient with a wearable wherein said wearable        comprises:        -   i) at least one electrode and/or optical sensor that, when            the wearable is fitted, is continuously or semi-continuously            monitoring the patient's heart rhythm;        -   ii) a CPU that collects and stores the heart rhythm data;            and        -   iii) a transmission component that connects to the data in            the CPU, wherein said transmission component is capable of            initiating a communication directly or indirectly to a            clinician wherein said data is optionally stored;    -   c) collecting and transmitting the heart rhythm data directly or        indirectly to said clinician who evaluates the data for the        presence and number of medium-long and/or long-duration episodes        of AFib and the extent of AFib burden;    -   d) qualifying said patient for budiodarone therapy if said data        evidence the requisite number of episodes of long duration AFib        and a requisite AFib burden.

In one embodiment, the CPU is also capable of evaluating the stored datato determine the presence and number of medium-long and/orlonger-duration episodes of AFib. Evaluation by the CPU can becontinuous or periodic. In another embodiment, the CPU can be programmedto alert the clinician and/or patient of medium-long and/orlonger-duration episodes of AFib.

In one embodiment, the patient is fitted with a wearable which can be apatch, a watch, a wristband, a strap, a ring, or any other device thatadheres to the body and can operate as described above. The wearableshould be engaged on the patient except for a period of temporarydisengagement such as for showering, swimming, changing batteries, etc.

In one embodiment, there is provided a method to assess if a qualifiedpatient on budiodarone therapy should be dose adjusted or disqualifiedwhich method comprises:

-   -   a) selecting a patient qualified for and is prescribed for        treatment with budiodarone by a clinician wherein said patient        is fitted with a wearable wherein said wearable comprises:        -   i) at least one electrode and/or optical sensor that, when            the wearable is fitted, continuously or semi-continuously            monitors the patient's heart rhythm;        -   ii) a CPU that collects and stores the heart rhythm data;            and        -   iii) a transmission component that connects to the data in            the CPU, wherein said transmission component is capable of            initiating a communication directly or indirectly to a            clinician wherein said data is optionally stored;    -   c) collecting and transmitting the heart rhythm data directly or        indirectly to said clinician where the data is evaluated for the        presence and number of long duration episodes of AFib and the        extent of AFib burden;    -   d) optionally adjusting the dosing of budiodarone to access        which dose is appropriate for that patient; and    -   e) assessing whether the collected data evidence that the        patient is or is not responsive to budiodarone therapy;

wherein said therapy is maintained for responsive patients and furtherwherein said therapy is terminated for non-responsive patients.

In yet another embodiment, patients who are initially responsive tobudiodarone therapy are continuously monitored to ensure that each ofsaid patients remains responsive to the dose of budiodarone. If not, theclinician can adjust the dose of budiodarone or discontinue budiodaronetherapy as appropriate.

In one embodiment of the above methods, the data is transmitted directlyor indirectly to the clinician who can assess the presence or absence ofmedium-long and/or longer-duration AFib, and optionally the extent ofAFib burden. The data can be stored and/or analyzed at a centralanalysis center, such as a “cloud” laboratory or similar site (such as aCORE laboratory), where a qualified health care professional can analyzethe data and advise the attending clinician as to the patient's responseand recommended adjustments to the therapy. In short, these preferredmethods allow for remote patient monitoring (RPM), where the patient hasno longer has responsibilities such as mailing patches for analysisand/or visiting the doctor's office.

In one embodiment, the requisite number of long duration AFib episodesand requisite extent of AFib burden to qualify for budiodaronepharmacotherapy may comprise one or more of long duration AFib episodes(e.g., at least a threshold number) of one or more minimum lengths(e.g., at least 1 hour, at least 5 hours, at least 24 hours, etc.) overa time period (e.g., over two weeks, a month, two months, etc.). As anillustrative example, the requisite number of long duration AFibepisodes may comprise at least one episode of AFib lasting more than 5hours over a month and/or at least two episodes of AFib lasting morethan 1 hour over a month. A requisite extent of AFib burden may be atleast a minimum extent of AFib burden (e.g., 0%—no required AFib burden,1%, 2%, etc.). The requisite number of long duration AFib episodes andrequisite extent of AFib burden may be set as is appropriate. Specificexamples as part of a non-exhastive list are provided in Table 2 below:

TABLE 2 # of long duration AFib episodes AFib burden Embodiment 1 Atleast 1 episode > 5 hours/month 2.5% or greater or at least 2 episodes >1 hour per month Embodiment 2 At least 1 episode > 5 hours/month 5% orgreater or at least 2 episodes > 1 hour per month Embodiment 3 At least1 episode > 5 hours/month 2.5% or greater Embodiment 4 At least 1episode > 5 hours/month 5% or greater Embodiment 5 At least 2 episodes >1 hour per month 2.5% or greater Embodiment 6 At least 2 episodes > 1hour per month 5% or greater

In one embodiment, the wearable may comprise a storage unit for storingcollected data, and the storage unit can be programmed to evaluate thestored data and alert the clinician or central analysis center of anypotentially harmful heart rhythm irregularities. The collected and/orevaluated data may be continuously or periodically reviewed by theclinician or health care professional (e.g., may be pushed to acomputing device accessible by the clinician continuously orperiodically, and/or pulled based on a request by the computing deviceaccessible by the clinician). Periodic evaluation can be, for example,once a day, once a week, twice a month, once a month, etc. The datacollection process may be continued indefinitely, e.g., until theclinician determines that the patient's heart rhythm data either meetsor fails to meet the requisite number of episodes of long duration AFiband/or the requisite extent of AFib burden. Preferably, data collectioncontinues for at least 14 days, 30 days, 45 days, 2 months, or at least12 weeks, or at the discretion of the attending clinician based on thehistory and risk factors of the patient. Patients who fail to meetestablished criteria for qualification are not included in budiodaronetherapy.

In one embodiment, qualified patients are placed on budiodarone therapy.Such therapy includes the administration of budiodarone or apharmaceutical composition comprising budiodarone twice a day (bid) inan amount ranging from about 200 mg bid to about 800 mg bid. Thepreferred dosing includes an escalating amount of budiodarone where thepatient is initially dosed at 200 mg budiodarone bid. Responsivepatients remain on that dose whereas non-responsive patients are doseadjusted in 200 mg increments until the patient either becomesresponsive or the patient is non-responsive at all tested dose levels.In the latter case, the patient is disqualified from budiodaronetherapy. In one embodiment, the qualified patients so treated arerefractory to one or more other methods for treating their AFib.

The serum half-life of budiodarone is about 6 to 7 hours afteradministration. As a general rule, a steady state concentration of adrug is about 5× the serum half-life. In this case, the steady statewould be about 30 to 35 hours. Once a steady state is achieved andallowing time for the drug to act, it is possible to initiate monitoringof a patient's heart rhythm at any point thereafter including about 3days after initiation of therapy and preferably at least 14 days afterinitiation of budiodarone therapy. The latter is preferred as it allowssufficient time for the drug to be effective.

In one embodiment, the wearable is a watch, a strap, a wrist band, aring, or a strap. In one embodiment, the watch is a smart watch.

In one embodiment, there is provided a method for reducing the risk of apatient progressing from paroxysmal AFib to persistent AFib or frompersistent AFib to permanent AFib, which method comprises:

identifying a patient with either paroxysmal or persistent AFib havingan AFib burden of at least 2.5% coupled with at least one episode oflong duration AFib over a 4-week period;

administering budiodarone to said patient;

monitoring the efficacy of said administration and optionally adjustingthe dose as needed to achieve a reduction in either or both AFib burdenand long duration AFib whereupon the risk of progression from paroxysmalAFib to persistent AFib or from persistent AFib to permanent AFib isreduced; and

maintaining said monitoring to confirm the continued efficacy ofbudiodarone.

In one embodiment, there is provided a method for reducing the risk ofheart failure in a patient diagnosed with paroxysmal AFib or persistentAFib, which method comprises:

identifying a patient with either paroxysmal or persistent AFib havingan AFib burden of at least 2.5% coupled with at least one episode oflong duration AFib over a 4-week period;

administering budiodarone to said patient;

monitoring the efficacy of said administration and optionally adjustingthe dose as needed to achieve a reduction in either or both AFib burdenand long duration AFib whereupon the risk of heart failure in saidpatient is reduced; and

maintaining said monitoring to confirm the continued efficacy ofbudiodarone.

In one embodiment, there is provided a method for reducing the risk ofstroke in a patient diagnosed with paroxysmal AFib or persistent AFib,which method comprises:

-   -   identifying a patient with either paroxysmal or persistent AFib        having an AFib burden of at least 2.5% coupled with at least one        episode of long duration AFib over a 4-week period;    -   administering budiodarone to said patient;    -   monitoring the efficacy of said administration and optionally        adjusting the dose as needed to achieve a reduction in either or        both AFib burden and long duration AFib whereupon the risk of        stroke in said patient is reduced;    -   maintaining said monitoring to confirm the continued efficacy of        budiodarone.

In another embodiment, there is provided a method for reducing the riskof stroke or congestive heart failure in a patient with paroxysmal AFibor persistent AFib wherein said AFib is treated with a pharmaceuticalwhich method comprises:

-   -   a clinician obtaining a patient's heart rhythm data from a        wearable engaged by the patient wherein said wearable comprises    -   a) at least one electrode or optical sensor that continuously or        semi-continuously monitors heart rhythm;    -   b) a transmission device capable of initiating transmission of        data;    -   c) circuitry that connects the two; and    -   d) a CPU that collects and stores the heart rhythm data,    -   said clinician conducts an evaluation of said data to determine        the effectiveness of the pharmaceutical by correlating the        presence or absence of episodes of long duration AFib to the        dose of the pharmaceutical used;    -   said clinician confirms that the dose of the pharmaceutical is        effective or ineffective in reducing or elimination episodes of        long duration AFib; and    -   if ineffective, said clinician increases the dose of the        pharmaceutical one or more times until said dose is effective        thereby reducing the risk of stroke or congestive heart failure        provided that if said pharmaceutical remains ineffective when        the maximum dose of said pharmaceutical is reached, said patient        is removed from treatment with said pharmaceutical.

In another embodiment, there is provided a method for reducing the riskof stroke or heart failure in a patient diagnosed with AFib and treatedwith budiodarone which inhibits episodes of long duration AFib in saidpatient which method comprises:

-   -   evaluation by a clinician of the patient's heart rhythm data        collected by a wearable and transmitted to said clinician from a        wearable engaged by said patient wherein said wearable        comprises:        -   a) at least one electrode or optical sensor that            continuously or semi-continuously monitors heart rhythm;        -   b) a transmission device;        -   c) circuitry that connects the two; and        -   d) a CPU that            -   i) collects the heart rhythm data and evaluates said                data for the presence of long duration episodes of AFib;                and            -   ii) stores the data; and    -   adjusting the dose of budiodarone as deemed necessary by the        attending clinician in order to reduce further episodes of long        duration AFib thereby reducing the risk of stroke or heart        failure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a chart indicating how the patient's AFib data isused in conjunction with treatment with budiodarone; and

FIG. 2 illustrates a cardiogram of a patient with intermittent AFib.

DETAILED DESCRIPTION

This disclosure is directed to methods for monitoring the heart rhythmof patients diagnosed with atrial fibrillation (AFib). Such monitoringallows for modifications to the patient's treatment thereby reducing therisk of stroke and/or heart failure. However, prior to discussing thedisclosure in more detail, the following terms will first be defined.Terms that are not defined are given their definition in context or aregiven their medically acceptable definition.

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting. As used herein, thesingular forms “a”, “an”, and “the” are intended to include the pluralforms as well, unless the context clearly indicates otherwise.

Definitions

As used herein, the term “optional” or “optionally” means that thesubsequently described event or circumstance may or may not occur, andthat the description includes instances where the event or circumstanceoccurs and instances where it does not.

As used herein, the term “about” when used before a numericaldesignation, e.g., temperature, time, amount, concentration, and suchother, including a range, indicates approximations which may vary by (+)or (−) 15%, 10%, 5%, 1%, or any subrange and/or value there between.Preferably, the term “about” when used with regard to a dose amountmeans that the dose may vary by +/−10%.

As used herein, the term “comprising” or “comprises” is intended to meanthat the compositions or methods include the recited elements, but donot exclude others.

As used herein, the term “consisting essentially of” when used to definecompositions and methods, shall mean excluding other elements of anyessential significance to the combination for the stated purpose. Thus,a composition consisting essentially of the elements as defined herein,or a method consisting essentially of the steps as defined herein, wouldnot exclude other materials that do not materially affect the basic andnovel characteristic(s) of the claimed subject matter.

As used herein, the term “consisting of” shall mean excluding more thantrace elements of other ingredients or substantial method steps.Embodiments defined by each of these transition terms are within thescope of this disclosure.

As used herein, the term “AFib” or “atrial fibrillation” refers to allvariants of atrial fibrillation except permanent AFib. Such variantsinclude but are not limited to paroxysmal AFib, persistent AFib, as wellas paroxysmal AFib and persistent AFib with low CHA2DS2-VASc scores (2or less) and high CHA2DS2-VASc scores (3 or higher). CHA2DS2-VASc scoresstand for congestive heart failure, hypertension, age ≥75 (doubled),diabetes, stroke (doubled), vascular disease, age 65 to 74, and sexcategory (female) and are clinical prediction rules for estimating therisk of stroke in people with non-rheumatic atrial fibrillation (AF). ACHA2DS2-VASc score comprises a point for each of the constituent riskfactors, or 2 points were indicated as (doubled).

As used herein, the term “long duration AFib” relates to a length oftime an episode of AFib lasts in a patient. This length relates to therisk of stroke and/or heart failure. As is apparent, the longer thelength of time a patient is in AFib, the higher the risk becomes. So, inone embodiment, a long duration AFib is any AFib episode lasting over 1hour, provided that the AFib is not permanent. In turn, long durationAFib is further categorized by the subsets “medium-long duration” AFib,which is about 24 hours or less in duration (i.e., over 1 hour and up to24 hours) and “longer-duration” AFib, which includes AFib episodes ofover 24 hours, but which are not permanent AFib.

As used herein, the term “continuous” or “continuously” refers tomonitoring conducted constantly during the engagement of a wearable bythe patient. Included within the term “continuous” or “continuously” arewearables that constantly monitor the heart rhythm when worn andpowered, but which may be taken off for limited periods of time (e.g.,changing batteries, bathing, etc.).

As used herein, the term “semi-continuous” or “semi-continuously” refersto monitoring that is automatically done periodically by the wearable ona set schedule (e.g., every 15 seconds, every 30 seconds, every minute,and the like) without the patient's activation of the wearable. The setschedule a schedule designed to be able to monitor heart rhythm with atemporal resolution sufficient to detect AFib episodes and/or to allowdetermination of lengths of long duration AFib episodes.

As used herein, the terms “engageable” means that the patient can placethe wearable on and off his/her body and initiate monitoring without theneed for assistance from an attending health care professional. As such,engageable wearables do not include implanted (invasive) devices such aspacemakers.

As used herein, the term “monitoring the heart rhythm” means anyevaluation that can be made of a patient's heart rhythm including thepulse rate, any aspect of the electric field of the patient's heart, andthe like provided that such monitoring is capable of ascertaining whenthe patient is experiencing AFib.

As used herein, the term “initiate monitoring” includes both automaticinitiation and physical initiation. “Automatic initiation” occurs whenthe wearable, once placed on the patient, automatically startsmonitoring without any further action by the patient. “Physicalinitiation” means that the patient is required to activate themonitoring by physically or verbally interacting with the wearable(e.g., push a button, provide a voice command, and the like).

As used herein, the term “transmission device” means any device capableof transmitting data from the wearable. The transmission device may beincluded in the wearable or may be a separate device that is incommunication with the wearable. The separate device can be a smartphone, a computer such as a pad, a laptop, or a desktop, and the like.

As used herein, the term “clinician” refers to a healthcare professionalqualified to ascertain whether a patient's heart rhythm data correlatesto sinus rhythm, atrial fibrillation, or other types of arrhythmias.

As used herein, the term “attending clinician” refers to the healthcareprofessional who is treating the patient with AFib. Such an attendingclinician is typically a doctor or a nurse practitioner.

The term “directly” as it relates to the transmission of the patient'sheart rhythm data refers to a transmission that is received by theattending clinician for evaluation regardless of whether thetransmission was deposited in a Cloud site or through a number ofservers, etc.

The term “indirectly” as it relates to the transmission of the patient'sheart rhythm data refers to transmission to a clinician who evaluatesthe data and provides either the data or the conclusions reachedregarding the data to the attending clinician. In such a case, theclinician can be a healthcare professional employed by a centralanalysis center or by the attending clinician, etc. to evaluate theheart rhythm data and provide instructions to the attending clinicianeither on an ongoing basis or when a change in the patient's conditionwarrants contact. In one embodiment, the clinician is employed by acentral analysis center, a facility that reviews the data generated byits instruments and renders a diagnosis and/or recommendation that istransmitted to the attending clinician. The central analysis center hasexpertise in the instrument, the data generated, and the ability toanalyze that data.

As used herein, a patient who is “responsive to budiodarone therapy”evidences a reduction in the number and/or duration of episodes of longduration AFib. The reduction may be a reduction by at least a certainpercentage (e.g., at least 10%, preferably at least 20%, more preferablyat least 30%, more preferably at least 40%, more preferably at least50%, etc.) of one or more of the number of episodes of long durationAFib episodes and/or the duration of episodes of long duration AFib. Inone embodiment, a responsive patient is a patient that evidences atleast a 10% reduction in at least one of the following when measuredover a 12-week period:

-   -   a) the number of long duration episodes of AFib lasting over 24        hours as compared to the number determined during qualification;    -   b) the number of long duration episodes of AFib lasting over 5        hours as compared to the number determined during qualification;    -   c) the number of long duration episodes of AFib lasting over 1        hour as compared to the number determined during qualification;        or    -   d) a reduction in AFib burden as compared to the burden        determined during qualification.        In still other embodiments, the responsive patient exhibits at        least a 20% reduction, at least a 30% reduction, at least a 40%        reduction, at least a 50% reduction, and/or at least a 60%        reduction in one or more of a-d above over a 12 week period.

As used herein, “other methods to treat AFib” may comprise one or moreblood thinners and/or other clot prevention measures, heart rate controlmeasures, and/or heart rhythm control measures. Examples of such methodsto treat AFib may include beta blockers (e.g., atenolol, bisoprolol,carvedilol, metoprolol, propranolol, timolol), Calcium channel blockers(verapamil, diltiazem), blood thinners (warfarin, coumarin, Jantoven,aspirin, apixaban, dabigatran, enoxaparin, heparin, rivaroxaban), sodiumchannel blockers (e.g., flecainide, propafenone, quinidine), potassiumchannel blockers (e.g., amiodarone, dofetilide, sotalol).

A patient may be deemed “refractory to one or more prior methods totreat their AFib” or “refractory to one or more other methods to treattheir AFib” if they have been treated with the one or more prior and/orother methods to treat AFib (e.g., the other methods to treat AFib, asdefined above), and their AFib has been deemed unresponsive and/orinsufficiently responsive, and/or of decreasing responsiveness to theone or more methods. The “one or more prior therapies” may be ongoingand/or may have been terminated.

As used herein, the term “smart” refers to computational abilities of adevice. The computational abilities of smart devices discussed hereinmay allow for user interaction (e.g., via a touchscreen) and/or forrunning applications on the smart device.

As used herein, the term “an AFib burden of at least 2.5%” means that inthe absence of therapy according to the present disclosure (e.g.,treatment with budiodarone and/or other heart rhythm drug), the patienthas episodes of AFib where the aggregate of the duration of each episodeover a set period of time is at least 2.5% of the total amount of timein said set period. So, for a patient monitored for 20 days (or 480hours), at least 2.5% AFib burden means that the total (cumulative)period of time where the patient experiences one or more episodes ofAFib is at least 12 hours (2.5% of 480 hours). This AFib burden may beindependent of the number, if any, of episodes of long duration AFib. Assuch, the one or more episodes of AFib that in the aggregate total atleast 12 hours can be a single episode or many episodes of less than 1hour each.

As used herein, the term “budiodarone” refers to(S)-sec-butyl2-(3-(4-(2-(diethylamino)ethoxy)-3,5-diiodobenzoyl)benzofuran-2-yl)acetate as well aspharmaceutically acceptable salts thereof. Budiodarone is represented bythe following formula:

as well as pharmaceutically acceptable salts thereof.

The term “wearable” refers to any device that can be worn by a user,e.g., as an accessory, as clothing and/or embedded in clothing, etc. Inan embodiment, a wearable device herein may be capable of measuring theheart rhythm of a user thereof without implantation (such as surgicaland/or subcutaneous implants).

As used herein, a patient is “fitted with a wearable” when the wearableis being worn by, or is otherwise fixed to, the patient so as to be ableto measure the heart rhythm of the patient.

As used herein, the term “baseline” refers to a patient who has AFib andis monitored to determine the extent of AFib burden and the number ofepisodes of long duration AFib over a set period of time prior totreatment with budiodarone. In such a case, measuring the baseline priorto therapy over a set period of time provides for the current state ofthe disease. In most if not all cases, the baseline state of the diseaseis unknown to the attending clinician and is necessary information todetermine if subsequent treatment with budiodarone is effective.

Instrumentation

The instrumentation used in the methods described herein may be used forpharmacotherapy as described herein, as opposed to merely for diagnosis.Using wearables merely for diagnosis is conventional and aims to informthe clinician whether the patient either has AFib or not and/or, if thepatient has AFib, possibly information about the patient's AFib burdenand the number of episodes of AFib. Such diagnostic analysis fails toaddress any pharmacotherapeutic suitability, efficacy, and/or dose,which extend beyond diagnosis. The pharmacotherapeutic methods describedherein include identifying patients who qualify for drug therapy and/ormonitoring the qualified patient during treatment with thepharmacotherapy to assess the drug's effectiveness (e.g., in reducingthe number of episodes of long duration AFib). The monitoring may allowfor dose adjusting for the patient until the patient is deemed to beresponsive to therapy or is disqualified from pharmacotherapy due to afailure to respond. The pharmacotherapeutic methods described herein mayprovide for limited (e.g., one or more periods of a discrete period,such as a period of about two or four or six weeks) and/or indefinite(e.g., without a preset end-date) monitoring of the patient to establishqualification for drug intervention and/or to ensure that the patient isand/or remains responsive. Accordingly, the wearables described hereinare designed and/or selected to be robust for extended use, and/orcomfortable and/or easy to use by the patient.

In practice, the wearable may include a cardiac monitoring component,which may be either an assisted or an unassisted component, formeasuring heart rhythm in patients. The wearable may be engageable anddisengageable by the patient and do not involve invasive procedurescommon to non-wearables, such as pacemakers, implantable cardioverterdefibrillators (ICD), and the like. The specific cardiac monitoringcomponent employed in the wearable is not critical, provided it canaccurately measure the heart rhythm. The wearable may be capable ofreporting measured heart rhythm data, such as by generating and/ortransmitting data indicating a length of time of a detected period ofAFib, and/or by generating and/or transmitting data indicating a numberof episodes of long duration AFib detected (e.g., over a time period ofinterest, such as a week, a month, etc.). Also, or alternatively, thewearable may be configured to transmit heart rhythm data to a deviceconfigured to detect AFib and/or determine a length of time of adetected period of AFib and/or a number of episodes of long durationAFib (e.g., over the time period of interest). The wearable is approvedby one or more regulatory bodies, such as the US Food & DrugAdministration (FDA).

Assisted Components

An assisted cardiac monitoring component may use photoplethysmography(PPG) to detect heart rate and rhythm. PPG is a conventional technologyfound in standard oximeters, measures light reflection in tissue todetect arterial pulsations and, accordingly, heart rhythm patterns.However, to continuously and/or semi-continuously measure heart rhythm,one must account for the fact that PPG signals generated during patientmovement are often distorted, weak and noisy. To account for suchdeficiencies, an algorithm may be used to reduce enough of thedistortion and/or noise to provide for a reliable signal. In oneembodiment, both a PPG sensor and accelerometer are employed with analgorithm that allows for appropriate (e.g., sufficient signal to noiseratio). When so assisted, PPG may allow for a reliable detection of bothheart rates and heart rhythm. See, for example, Wojcikowski, et al.,Photoplethysmographic time-domain heart rate measurement algorithm forresource-constrained wearable devices and its implementation, Sensors20, no. 6 (2020): 1783 which is incorporated herein by reference in itsentirety.

In some embodiments, the cardiac monitor component uses piezoelectricmaterial and/or rhythm electroactive polymers to detect blood flow,thereby indirectly measuring heart rhythm.

In some embodiments, a combination of PPG and/or piezoelectricmeasurements and electrocardiogram data from single-electrode wearables(iECG, as opposed to ECG, which will refer to a conventionalmultiple-electrode electrocardiogram) can be combined in order toincrease the specificity of the measurement. The iECG and the PPG or thepiezoelectric data can originate either from two separate devicescommunicating by transceivers, for example, an armband and a smartwatch,or they can originate from a single device, for example, a wrist band ona smartwatch (for example, the Kardia Band on an iWatch). Once anarrhythmia is detected in the PPG data, the corresponding (e.g., intime) iECG data may be analyzed by an algorithm.

Unassisted Components

in another embodiment, the wearable may include an unassisted cardiacmonitor component, such as a portable electrocardiogram. The portableelectrocardiogram component may be wearable, engageable at will by thepatient, and/or capable of transmitting data, e.g., via a built-inantenna. The wearable comprising the unassisted cardiac monitorcomponent is able to measure heart rates and heart rhythms. The wearablemay be configured to detect and log AFib burden and/or long duration(episode) of AFib (LEAF) over an observation period (e.g., of about 2weeks or longer). The unassisted cardia monitor component employs directmeasurement, which means that the device is reading electrical signalsgenerated by the heart. The direct measurement may be less affected bynoise and distortion than indirect measurements, such as PPGmeasurements, which may enable transmitting measurement data to aclinician without the use of an algorithm, and/or with reduced use ofany algorithm or data processing.

In some embodiments, the wearable may include a specialized accessory,such as a cardiac monitor device, that can detect the electricalactivities of a heart including heart rhythm through an electrode. Thespecialized accessory may be capable of initiating transmission and/ormay comprise and/or be connected to a transmission device.

In some embodiments, the cardiac monitor device can be a component thatis an integral part of a single wearable device, such as a smart watch.By providing a single device that is wearable by a user and is capableof monitoring the electric field of the heart of the user, theelectrical activities of the heart can be monitored continuously over aprolonged period, such as days or even months.

In some embodiments, the cardiac monitor device may include ananalog-to-digital convertor capable of digitalizing measured electricfield data (e.g., measured potential difference data) so as to transmitand/or stored in memory the measured data as digitized data. The cardiacmonitor device can include an output that can transmit signals carryinginformation about the difference of potential between the limb and thebody to an external circuit. The output can take various forms. In onecase, the output can be a transceiver that communicates to anothertransceiver/receiver in another unit, for example, a watch or a tablet.In one embodiment a central analysis center (e.g., a remote lab, such asa CORE lab and/or a remote data analysis center and/or a server) mayinterpret and/or summarize the AFib data and/or the LEAF data. Thecentral analysis center may also transmit a dose adjustmentrecommendation to the treating clinician, without a need for the patientto visit his or her physician (e.g., as part of a patient monitoringprogram). Also, or alternatively, an artificial intelligence algorithmmay be used to determine the dose adjustment, and may transmit the doseadjustment recommendation to the physician.

Further Aspects

In one embodiment, the wearable may be a small consumer electronicdevice, for example, a watch, an armband, a ring, a strap, and/or awrist band. The wearable may include a housing that carries the cardiacmonitor component and any associated circuitry, CPU, and the like. Thewearable can also be worn at other locations on the user, including, butnot limited to, the wrist, leg, neck, and/or body. The wearable maycomprise a specialized accessory capable of communicating with anotherelectronic device such as a tablet, a laptop computer, a desktopcomputer, and/or other similar devices, which, in turn, can communicateto a cloud network to transmitted information from the device to theclinician. Also, or alternatively, the specialized accessory may becapable of transmitting information directly and/or via a network to theclinician.

The heart rhythm and iECG wearables may be Bluetooth, Z-Wave, Zigbee,and/or Advanced and Adaptive Network Technology (ANT)-enabled. Forexample, the iECG and/or the heart rhythm monitoring and/or recordingdevice (e.g., a PPG or piezoelectric heart rhythm monitoring and/orrecording device) may be paired with an application that may beconfigured to automatically detect AFib based on data from the iECGand/or the heart rhythm monitoring and/or recording device. The iECGdevice and/or the rhythm monitoring and/or recording device may beconfigured to transmit data to the application. The data may betransmitted using one or more of Bluetooth, Z-Wave, Zigbee, or ANTprotocols. The application may be configured to analyze the data using aproprietary software. Based on the data from the iECG and/or the heartrhythm monitoring and/or recording device, the application may be ableto interpret and/or detect AFib with a sensitivity >90% and aspecificity >80%.

Patients with a wearable as described herein can use the wearable torecord heart rhythm and detect AFib. The recording can be continuousand/or semi-continuous. The specifics of the recording can be programmedinto the device, directly or indirectly (e.g., remotely). AFib data maybe stored securely, such as in a cloud-based data repository usinghighly secured protocols.

Examples of commercially available assisted and unassisted wearablesinclude, without limitation, the following:

-   -   MCOT® wearables sold by Philips Biosciences, Best, Netherlands.        This device is a wearable patch that can send iECG data        automatically via a wireless connection to a central analysis        center (e.g., a CORE lab). This system is configured to provide        data sufficient to enable a clinician to determine if dose        escalation and/or drug discontinuation is warranted.    -   An ePatch extended wear Holter monitoring system sold by Philips        Biosciences, Best, Netherlands. This device is configured to        record data indicating AFib and/or long duration (episode) of        AFib (LEAF). This device is configured to record and/or store        iECG data continuously. This data is then archived and analyzed        centrally.        There are a number of other wearables, some of which are FDA        approved, which can be used in placed of those recited above        including, by way of example only, Zio by iRhythmtech, San        Francisco, California, USA; Frontier X2, Fourth Frontier,        Austin, Texas, USA, wearables by VivaLink, Campbell, California,        USA, just to name a few. The above and other wearables discussed        herein represent a non-exhaustive list of wearables suitable for        use in the methods described herein. The specific wearable to be        used is not critical, as long as it is capable of measuring        heart rhythm (e.g., generating a signal and/or data from which        heart rhythm can be determined). The wearable used should be        capable of measuring the heart rhythm of a patient fitted with        the wearable continuously or semi-continuously for a required        time period as described herein (e.g. a required time period for        determining a baseline, for monitoring during pharmacotherapy,        etc.). Further, the wearable should be small enough and/or        comfortable enough for a patient to wear and/or be fitted with        the wearable for the required time period.        Methodology

The disclosed methods allow the attending clinician to identify and/ortreat a qualified patient with pharmacotherapy, as well as to assess theefficacy of the therapy based on heart rhythm data monitored over aperiod of time. The period of time may be an extended period of time,which may be measured in weeks, months, and/or years. The monitoring maycomprise monitoring heart rhythm data and/or using said heart rhythmdata to determine a condition of the patient's AFib, which may bedetermined based on one or more of the patient's AFib burden or thenumber or duration of AFib episodes over the period of time (e.g., afrequency of AFib episodes and/or long duration AFib episodes). Thisrepresents a new paradigm in treating AFib, as it allows the clinicianto do one or more of the following:

-   -   assess the extent of the disease in the patient;    -   determine if the patient qualifies for pharmacotherapy;    -   evaluate the efficacy of the therapy, in the short term (1-6        months) and/or in the long term (after 6 months);    -   dose adjust the patient to achieve and/or maintain a therapeutic        result; and/or    -   remove patients from pharmacotherapy if they are non-responsive        to the therapy.

In contrast thereto, conventional monitoring of a patient is typicallydiagnostic in nature, e.g., conducted during a single short-durationperiod typically of no more than two-weeks using a Holter monitor or theequivalent. Such diagnostic methods allow the clinician to at bestconfirm the presence of AFib. In most cases, the clinician will thenplace the patient on blood thinners. Alternatively, the clinician canplace a diagnosed patient on pharmacotherapy, which might involve heartrate reduction using beta-blockers and/or calcium channel blockers.Regardless, once diagnosed, conventional monitoring is typicallyterminated.

In cases where a clinical evaluation of AFib is done for clinicalinvestigative purposes, it is common to use an implantable (invasive)device that requires surgical insertion and, subsequently, surgicalremoval. Such investigations are typically done in order to understandthe underlying risks of stroke and congestive heart failure are relativeto either the AFib burden and/or AFib duration. See, for example,Turakhia M. P. et al., Circ Arrhythm Electrophysiol., 2015, 8(5):1040-7and many others. In some cases, non-invasive means to monitor thepatients were sometimes used but typically the monitoring is of shortduration. See, e.g., Go, et al., JAMA Cardiology, 2018, 3(7):601-608.Regardless, such clinical evaluations failed to address methods fordelivering budiodarone to a patient and then evaluating the effect ofthis drug on the patient's AFib burden or episodes of long duration AFibover extended periods of time with the option to dose adjust patients toachieve the desired therapeutic result.

Unlike prior protocols for treating AFib using drugs that limited thepatient's heart rate, the methods described herein are directed totreating the patient's heart rhythm in order to reduce the causativereasons for stroke and heart failure. By coupling the ability tocontinuously or semi-continuously monitor the heart rhythm with suitabledrugs that limit the number and extent of long duration episodes ofAFib, the clinician can significantly reduce the risk of stroke orcongestive heart failure. Still further, by monitoring the patient afterinitiation of drug therapy, the clinician can now evaluate the efficacyof the drug, adjust the dose as needed to enhance overall efficacy or toidentify those patients who are non-responders to such therapy who areremoved from the therapy.

One embodiment of this approach is depicted in FIG. 1 , whichschematizes an iterative process to evaluate a patient, qualify apatient for budiodarone therapy, and treat the qualified patient. InFIG. 1 , an exemplary cohort of patients, who have been diagnosed witheither paroxysmal and/or persistent AFib, are evaluated for their AFibburden. Those evidencing a suitable AFib burden (“Yes” at star decisionpoint), in this case, 5% or more, but this AFib burden may be adifferent threshold, such as 2.5%, and/or a patient and/or cohortspecific threshold, may be selected to continue in the qualificationprocess, while those who fail to meet this threshold are excluded (“No”at star decision point). The patients may also be evaluated for theduration of their AFib episodes. In this particular embodiment, patientsare further qualified for budiodarone therapy (“Yes” at star decisionpoint) if there is evidence of at least 1 episode of AFib lasting morethan 5 hours over a 1-month period and/or two or more episodes of AFiblasting more than 1 hour over a 1-month period. Patients who fail tomeet either of these criteria are excluded (“No” at star decision point)as presumably having a very low risk of stroke or congestive heartfailure. Qualified patients are placed on an ascending dose regimen ofbudiodarone, which has been shown to significantly reduce episodes ofAFib, including episodes of long duration AFib, which, by definition,reduce AFib burden. Other drugs that behave similarly to budiodarone maybe used in place of and/or in addition to budiodarone in the methodsdescribed herein.

In the iterative process of FIG. 1 , an ascending regimen is employed toassess whether budiodarone is effective in treating long durationepisodes of AFib and/or at what dose(s). Given that the AFib burdenand/or the number and duration of episodes of long duration AFib varyfrom patient to patient, different doses of budiodarone may be effectivefor different patients. However, heretofore, a clinician prescribingbudiodarone at a first dose was blinded from whether that dose wasefficacious. As per FIG. 1 and the Examples below, the methods describedherein allow the clinician to assess efficacy at a first dose and/or todose adjust in an ascending and/or descending protocol in an iterativeprocess until either a therapeutic result is achieved, and/or thepatient is deemed to be a non-responder. As to such non-responders, theyare removed from budiodarone therapy.

In an ascending regimen, patients are first administered a low dose andmay have the dose increased in case the patient is non-responsive and/orinsufficiently responsive (e.g., “No” at the plus signs). A patient maybe determined non-responsive if they do not respond to a maximum dosage.A descending regimen can also, or alternatively, be employed, in which ahighest dose of budiodarone is administered to the patient and efficacyis determined for decreasing dosages. One advantage of a descendingprotocol is that non-responders could be determined in the firstiteration and not the last. However, an ascending protocol may havebenefits of first finding a lowest effective dosage and/or reducing therisk of side-effects.

In one embodiment, treatment of a patient with budiodarone may result inreducing a number and/or frequency of episodes of long duration AFiband/or may result in reducing the AFib burden. This is in contrast todrugs that reduce heart rate but have little to no ability to reduce theduration AFib episodes and/or the AFib burden. AFib burden and episodesof long duration AFib are distinct. As to AFib burden, the number andduration of each AFib episode in a patient is measured to determine anAFib burden. A patient with a enough of only very short durationepisodes of AFib may still be assigned a higher AFib burden than apatient with infrequent episodes of long duration AFib. Hence, a patientwho has 8 episodes of AFib each having a duration of 45 minutes in agiven 24-hour period would be assigned a AFib burden of 25% (6 hours/24hours). In contrast thereto, a patient with a single episode of AFiblasting for 5 hours during a 24-hour period would be assigned an AFibburden of 20.8%. However, the latter patient with the single AFibepisode may be at greater risk of a stroke than the former patient.Accordingly, patients having an AFib burden of less than 2.5% are veryunlikely to have long duration AFib and, accordingly, may be determinednot qualified for treatment with budiodarone.

Still further, transitioning a patient from either paroxysmal AFib topersistent AFib or from persistent AFib to permanent AFib may beundesirable as it may evidence unwanted disease progression. Becausebudiodarone reduces the extent of long duration AFib and the number ofAFib episodes, the combination of these reductions inhibits theprogression of the disease and, in some cases, may revert such atransition.

In comparison, treatment of AFib with blood thinners does not addressthe cause of AFib, does not reduce the underlying concerns with eitherAFib burden and/or with episodes of medium duration and longer-durationAFib. Moreover, using blood thinners does not prevent a patient fromprogressing from paroxysmal AFib to persistent AFib or from persistentAFib to permanent AFib. Still further, the use of blood thinnersintroduces another set of issues with bleeding, such as bleeding thatleads to death.

In view of the above, according to the present disclosure, a patient'sheart rhythm may be monitored over an extended period to assess theefficacy of a drug that is intended to control such long durationepisodes. Devices such as a Holter monitor can be used to monitor apatient's heart rhythm over a short period of time (e.g., 1 day, 2 days,or 3 days and even up 14 days), but such monitoring cannot provide acomprehensive and ongoing analysis of the patient's AFib and/or how adrug treatment is impacting the number and duration of episodes of AFibover extended periods of time (e.g., of weeks or more). Suchshort-duration analysis provides only a diagnostic analysis, not atherapeutic analysis, and fails to provide a full picture of the hearthealth of the patient. Due to the erratic and dynamic nature of AFib,and variability across patients, an accurate measurement of AFib in apatient can only be obtained by monitoring over prolonged periods oftime, such as longer than 1 month, longer than 3 months, etc.

Drug Therapy

There are many conditions where the attending clinician can evaluate apatient based on a static number that represents a meaningful long-termaverage. For example, in diabetes, the three-month value for hemoglobinA1C (also referred to as HbA1C test is a blood test) provides anexcellent indicium for the average daily blood glucose levels. Inaddition, liver function, prostate health, thyroid health, etc. can allbe evaluated based on a specific number that provides meaningfulinformation to the clinician.

The clinicians treating paroxysmal and/or persistent AFib have had torely upon brief monitoring of the patient's heart rhythm, such as an ECG(electrocardiogram) and/or a Holter monitor. However, such briefmonitoring may miss critical data points that could only be obtained bymonitoring over longer periods of time. This may cause a clinician toavoid pharmacotherapy without a means to monitor the drug'seffectiveness in the patient. Rather, a patient diagnosed with AFib maybe placed on symptom and/or risk reduction treatments, such as bloodthinners. However, while blood thinners will reduce the risk ofclot-related strokes (e.g., clots arising from AFib), there is acorresponding increased risk of uncontrolled bleeding which can lead todeath.

Pharmaceuticals, such as sotalol, as well as beta-blockers and calciumchannel blockers, have been used to treat AFib. Examples of calciumchannel blockers include amlodipine, diltiazem, felodipine, isradipine,nicardipine, nifedipine, nisoldipine, and verapamil. Examples of betablockers include acebutolol, atenolol, bisoprolol, metoprolol, nadolol,nebivolol, and propranolol. Drugs with combined modes of action, such asamiodarone, also exist. Budiodarone, a drug with a combined mode ofaction, has been shown to reduce episodes of long duration AFib withouta significant increase in the QT interval. Indeed, budiodaronerepresents a significant advancement in treatment for AFib, sinceepisodes of long duration AFib are substantially the cause of clotformation that may lead to strokes and/or congestive heart failure.However, AFib is a variable disease, with some patients requiringdifferent dosing of a drug to achieve desired results. As noted earlier,the inability to monitor patients in a manner that could evaluate theeffectiveness of the drug was a major drawback to pharmaceuticalintervention. This has led to clinicians opting for the use of bloodthinners and/or risk reduction measures, instead of proactivepharmaceutical intervention.

The wearables and methods described herein provide sufficient data tothe clinician on an ongoing basis to determine the long-termeffectiveness of drugs in treating paroxysmal and persistent AFib. Assuch, methods that integrate data generated by wearables with a drugthat can control long duration AFib and/or reduce AFib burden may allowfor more effective treatment of AFib, which is a long felt need in theart. Moreover, the ability to determine the long-term effectiveness of adrug may allow for dose-adjusting the patient to effectively achievecontrol over episodes of long duration of AFib.

Treatment Regimens using Budiodarone

Budiodarone has been shown to reduce episodes of long duration AFib inpatients thereby reducing the risk of stroke and congestive heartfailure. However, to effect therapy over a broad spectrum of patientshaving varying frequencies in the number and duration of episodes oflong duration of AFib using budiodarone requires that the clinicianmonitor each patient for efficacy at a given dose. Such represents apersonalized medicine approach to a disease that is treatable bybudiodarone.

If a patient is non-responsive at that dose, an increase in dosing iswarranted and the process is repeated until it is determined that thepatient is responsive at a given higher dose or is non-responsive.Patients who are non-responsive at all tested doses are removed frombudiodarone therapy.

Still further, patients who have either paroxysmal or persistent AFiband, who are refractory to one or more prior methods for treating theirdisease, may be candidates for the methods and procedures describedherein. Such patients may be screened (qualified) for treatment bydetermining their baseline AFib burden and/or the number and extent oftheir long duration AFib episodes. Their baseline may also be used toassess the relative reduction in and/or the complete elimination ofthese symptoms based on budiodarone therapy and/or to identify patientsas non-responders to budiodarone therapy. Accordingly, a method to treatpatients with paroxysmal or persistent AFib, wherein said patients arerefractory to one or more prior therapies to treat their AFib, maycomprise:

-   -   a) selecting a patient who is refractory to the one or more        prior methods to treat AFib;    -   b) identifying the number of episodes of long duration AFib and        the extent of their AFib burden, wherein the identified number        and extent satisfy criteria to qualify the patient for treatment        with budiodarone by a clinician;    -   c) fitting said patient with a wearable, wherein said wearable        comprises:        -   i) at least one electrode and/or optical sensor that, when            the wearable is fitted, continuously or semi-continuously            monitors the patient's heart rhythm;        -   ii) a CPU that collects and stores the heart rhythm data;            and        -   iii) a transmission component configured to access the data            in the CPU, wherein said transmission component is capable            of initiating a communication directly or indirectly to a            clinician;    -   d) causing collecting and transmitting of the heart rhythm data        directly or indirectly to a clinician, where the data is        evaluated for the presence and number of long duration episodes        of AFib and the extent of AFib burden;    -   d) optionally adjusting the dosing of budiodarone to determine        an appropriate dose for the patient; and    -   e) assessing whether the collected data evidence that the        patient is or is not responsive to budiodarone therapy;

wherein said therapy is maintained for responsive patients and furtherwherein said therapy is terminated for non-responsive patients.

Because of the lack of sufficient information to ascertain the efficacyfor a given dose of any drug prescribed to reduce the number of episodesof long duration AFib in the treated patient, a clinician wouldinvariably avoid doing so particularly given the variability in patientsas well as in the disease itself. Still further, many clinicians viewthat treating (reducing) the heart rate as an appropriate method fortreating AFib optionally coupled with blood thinners. See, for example,Atrial Fibrillation—Treatment,https://www.nhs.uk/conditions/atrial-fibrillation/treatment/where, in2021, the authors were controlling heart rates as part of an appropriateapproach to treating AFib. Taken together, the use of a wearable thatcould generate data as to a patient's response to a given dose ofbudiodarone over an extended period of time was not contemplated. Now,as per the methods described herein, a clinician can evaluate apatient's heart rhythm data over at least 2 weeks, over at least 1month, over at least 3 months, and/or over at least 6 months andpotentially for the remainder of the patient's life, so as to determinethe number and/or duration of episodes of long duration AFib; based onthat determination assess whether the patient should be placed onbudiodarone therapy; and, if so, assess the patient's response tovarying doses of budiodarone.

In one embodiment, which is illustrated in the Examples and FIG. 1 , forexample, the clinician may initiate dosing of budiodarone at a minimallevel of about 200 mg twice a day (bid) and then assess whether thatdose is effective in eliminating episodes of long duration AFib. Theclinician can review data at the initial dosing level and dose-adjustone or more times, e.g., as necessary to arrive at a dose where thepatient is substantially free of and/or is free of episodes of longduration AFib. In general, the incremental increases in dosing can beabout 200 mg twice a day. So, in this approach, the dosing can bechanged from about 200 mg bid, to about 400 mg bid, or to about 600 mgbid, and so on up to about 800 mg bid and possibly higher if theattending clinician determines that there is a benefit to higher doses.

Systems

The methods described herein can be conducted either in a unitarydevice, such as a wearable that has the ability to record, store andtransmit the heart rhythm data. However, systems of multiple devices canalso be used, provided that such systems include:

-   -   a) a wearable that collects heart rhythm data from a patient        diagnosed with either paroxysmal atrial fibrillation and/or        persistent atrial fibrillation;    -   b) a CPU that is in communication with the wearable that        collects and stores the data; and    -   c) a transmission device that communicates with the CPU and that        sends the data directly and/or indirectly to one or more        designated recipients.

EXAMPLES

In the examples that follow, and in the specification, the followingabbreviations have the following meanings. If an abbreviation isundefined, then it has its conventional medical meaning.

AFib or AF=atrial fibrillation

bid=twice a day

bpm=beats per minute

hrs=hours

mg=milligrams

PPG=photoplethysmography

SD=standard deviation

Example 1 is provided to illustrate that the use of a wearable candetect AFib episodes during continuous monitoring of a patient.

Examples 2-7 establish the utility of budiodarone in the methodsdescribed herein. In these examples, the patients all had surgicallyimplanted pacemakers and as such carried a number of risks associatedtherewith. See, e.g., Pacemaker,https://www.mayoclinic.org/tests-procedures/pacemaker/about/pac-20384689,(last visited Oct. 26, 2022) which is incorporated herein by referencein its entirety.

Example 1—Wearables that Detect AFib in Patients on a Continuous Basis

In this example, a male patient suffering from non-permanent AFib wasfitted with a MCOT wearable device sold by Philips BioSciences, Inc.,Best, The Netherlands and commercially available by prescription in theUnited States. The MCOT device employs PPG coupled with an algorithm toassess heart rhythm and AFib. The MCOT device is configured towirelessly and seamlessly provide heart rhythm and AFib data to adedicated computer.

The patient was continuously monitored over a period of 23.5 hrs. Duringthe entire period, the MCOT device measured the patient's heart rhythmand rate. FIG. 2 provides a cardiogram obtained during the monitoringperiod. Of note is that there were 33 separate episodes of AFib detectedand recorded each separated by periods of sinus rhythm or otherarrhythmias. The specific details of the analysis of the cardiogram areas follows:

Number of AFib Episodes 33 Longest Period in AFib 3 hours and 2 minutesHeart Rate (minimum/maximum) 48/94 beats per minute AFib Burden 36%The above data demonstrates that a wearable as described herein wascapable of continuously monitoring the patient heart rhythm and provideddetailed analysis of the number of AFib episodes as well as the extentof AFib burden.

Example 2—Elimination of Long Duration AFib with Budiodarone

This example is a clinical trial evaluation of budiodarone in treating 6patients with paroxysmal or persistent AFib who previously evidencedepisodes of long duration AFib (greater than 24 hours). In this example,the patients' heart rhythm was continuously monitored over a two-weekperiod with a pacemaker, and were treated with different doses ofbudiodarone. The purpose of this example is to establish whetherbudiodarone reduces long duration AFib lasting more than 24 hours. Thedifferent doses and results of this evaluation are provided in Table 3below:

TABLE 3 Parameter Mean (SD) 200 mg 400 mg 600 mg 800 mg Baseline Bid bidbid bid Washout # of AFib episodes 22 (22) 31 (28) 37 (54) 42 (66) 24(28) 37 (49) Duration of episodes 4.8 (5.2) 1.7 (2.5) 0.6 (0.7) 0.1(0.2) 0.5 (0.7) 2.5 (5.0) Duration of sinus 23 (21) 131 (162) 48 (57)103 (148) 42 (70) 40 (43) rhythm Longest AFib 50 7 13 7 5 105 Episode -hrs

The above results demonstrate that budiodarone eliminated over 70% ofthe episodes of long duration AFib lasting more than 24 hours ascompared to Baseline for all dose levels with little differences betweentreatment levels of 200 mg bid, 600 mg bid and 800 mg bid. In contrast,both baseline and washout results evidence the presence of episodes oflong duration AFib lasting more than 24 hours. These results alsoevidence a significant reduction (more than 64% reduction) in AFibburden (the number of episodes over a 2-week period times the averageduration of the episodes). This reduction correlates well with reducingthe risk of a patient transitioning from paroxysmal AFib to persistentAFib or from persistent AFib to permanent AFib.

Example 3—Elimination of Longer Duration AFib (>24 Hours) During a12-Week Period

This example is a clinical trial evaluation of budiodarone in treating 6patients with either paroxysmal or persistent AFib who previouslyevidenced episodes of long duration AFib (greater than 24 hrs). In thisexample, the patients' heart rhythms were continuously monitored over atwelve-week period with a pacemaker (surgically invasive procedure) andwere treated with different doses (2 weeks each) of budiodarone. Inaddition, during this trial, the patients were under continuousmonitoring and constant clinician supervision.

The purpose of this example is to establish whether budiodaronetreatment can reduce longer duration AFib (AFib episodes lasting morethan 24 hours) in a clinical study setting and using a pacemaker toevaluate heart rhythm. The results of this analysis are provided inTable 4 below:

TABLE 4 Episodes of AFib > 24 hrs Number Duration Off Drug (baseline) 4219 (100%) 200 mg bid 0 0 (0%) 400 mg bid 0 0 (0%) 600 mg bid 0 0 (0%)800 mg bid 0 0 (0%)

“Number” indicates the number of longer duration episodes of AFib (i.e.,having a duration of greater than 24 hours). “Duration” indicates theamount of time during the 2-week period spent in the longer durationindicated in hours and a percentage relative to the baselinemeasurement. As per the above results, 200 mg b.i.d. was sufficient totreat all patients in the study by eliminating the number of episodes ofAFib lasting over 24 hours. In this case, dose escalation was notrequired to improve patient efficacy as the 200 mg bid doses ofbudiodarone were sufficient to eliminate these long duration episodes ofAFib.

Example 4—Reduction of Long Duration AFib (>5 Hours) During a 12-WeekPeriod

This example is a clinical trial evaluation of budiodarone in treating 6patients with either paroxysmal or persistent AFib who previouslyevidenced episodes of long duration AFib (greater than 5 hrs). In thisexample, the patients' heart rhythms were continuously monitored over atwelve-week period with a pacemaker (surgically invasive procedure) andwere treated with different doses (2 weeks each) of budiodarone. Inaddition, during this trial, the patients were under continuousmonitoring and constant clinician supervision.

The purpose of this example is to establish whether budiodarone reduceslong duration AFib lasting more than 5 hours in a clinical study settingusing a pacemaker to evaluate the heart rhythm. The results of thisanalysis are provided in Table 5 below:

TABLE 5 Episodes of AFib > 5 hrs Number Duration Off Drug (baseline) 29490 (100%) 200 mg bid 3 17 (3.5%) 400 mg bid 4 38 (7.7%) 600 mg bid 2 14(2.8%) 800 mg bid 1 5 (1%)

“Number” indicates the number of long duration episodes of AFib having aduration of greater than 5 hours. “Duration” indicates the amount oftime during the 2 week period spent in the greater than 5 hour durationAFib, indicated in hours and a percentage relative to the baselinemeasurement. In this example, all doses of budiodarone providedsignificant benefits in reducing both the number and duration of AFibepisodes over 5 hours, with both the 200 mg bid and the 600 mg bidproviding similar results whereas the results for 400 mg bid wereexceptionally better than Off Drug condition, but inferior to the 200 mgbid and the 600 mg bid. Finally, the 800 mg bid performed best. In alldoses, the reduction in episodes of AFib of greater than 5 hours wereabove 85% and the corresponding reduction in AFib burden was above 90%.

In light of the previously discussed relation between long duration AFibepisodes and increase the risk of stroke and heart failure (see, e.g.,Singer, et al., Temporal Association Between Episodes of AtrialFibrillation and Risk of Ischemic Stroke, JAMA Cardiology,6(12):1364-1369 (2021)), the next comparative example measured thereduction in AFib episodes of 1 hour or more.

Example 5—Reduction of Long Duration AFib (>1 Hours) During a 12-WeekPeriod

This example is a clinical trial evaluation of budiodarone in treating 6patients with either paroxysmal or persistent AFib who previouslyevidenced episodes of long duration AFib (greater than 1 hour). In thisexample, the patients' heart rhythms were continuously monitored over atwelve-week period with a pacemaker (surgically invasive procedure) andwere treated with different doses (2 weeks each) of budiodarone. Inaddition, during this trial, the patients were under continuousmonitoring and constant clinician supervision.

The purpose of this example is to establish whether budiodarone reduceslong duration AFib (duration >1 hr) in a clinical study setting using apacemaker to evaluate the heart rhythm. The results of this analysis areprovided in Table 6 below:

TABLE 6 Episodes of AFib > 1 hrs Number Duration Off Drug (baseline) 66598 (100%) 200 mg bid 22 60 (10%) 400 mg bid 12 56 (9.3%) 600 mg bid 626 (4.3%) 800 mg bid 6 15 (2.5%)

This example demonstrates a substantial reduction in the number ofepisodes of long duration AFib (>1 hrs) over a 2 week period. As above,“Number” indicates a number of long duration AFib episodes during the 2week period, and “Duration” indicates a number of hours during the 2week period sent in the long duration AFib episodes

Example 6—Reduction in Episodes of AFib Greater than 6 Minutes During aTwelve Week Period

This example shows the robust nature of budiodarone in reducing bothAFib burden and episodes of AFib greater than 6 minutes (0.1 hour) in 6patients with either paroxysmal or persistent AFib and who previouslyevidenced episodes of long duration AFib (greater than 1 hr). In thisexample, the patients' heart rhythm was continuously monitored over atwelve-week period with a pacemaker. The patients were treated withdifferent doses (2 weeks each) of budiodarone. In addition, during thistrial, the patients were under continuous monitoring and cliniciansupervision.

The results of this example are summarized in Table 7 and establish thatbudiodarone not only reduces long duration AFib lasting more than 1 hourin a clinical study setting using a pacemaker to evaluate the heartrhythms, but also significantly lowers episodes of greater than 6minutes (0.1 hours).

TABLE 7 Duration Episodes of AFib > 0.1 hrs Number in hours Off Drug(baseline) 99 (100%) 616 (100%) 200 mg bid 52 (52%) 71 (11%) 400 mg bid28 (28%) 61 (10%) 600 mg bid 16 (16%) 30 (4.8%) 800 mg bid 15 (15%) 16(2.5%)

The “Number” indicates the number of AFib episodes greater than 6minutes for all tested patients over the trial period (4 weeks for basedline, 2 weeks experimental). The “Duration” in hours indicates thecumulative duration in hours over the trial period that the testedpatients were measured in episodes of AFib greater than 6 minutes. Theabove results demonstrate that not only does budiodarone reduce thenumber of episodes of long duration AFib, but also reduces shortepisodes of AFib, thereby providing further protection against strokeand heart failure and significantly reducing the AFib burden.

For patients with paroxysmal and persistent AFib with high CHA2DS2-VAScscores (3 or higher), AFib episodes of greater than 6 minutes can leadto an increased risk of stroke and/or congestive heart failure. The datain Table 7 evidence that, for all doses of budiodarone tested, thenumber of episodes of AFib longer than 6 minutes were reducedsignificantly, and at high concentrations of 600 mg bid or 800 mg bid,these episodes were reduced by more than 80%.

Table 8 provides a summary of the fraction of time and the number ofhours per week that the patients were in episodes of AFib greater than 6minutes in duration, on average. The percent time in AFib was reduced by90% for doses of budiodarone at 600 mg bid and 800 mg bid.

TABLE 8 Fraction of hours Duration in hrs/week Episodes of AFib > 0.1hrs (percent) (average per patient) Off Drug (baseline) 616/4032 (15%)25.2 200 mg bid 71/2016 (3.5%) 5.9 400 mg bid 61/2016 (3.0%) 5 600 mgbid 30/2016 (1.5%) 2.5 800 mg bid 16/2016 (0.8%) 1.3

The percent time in AFib for a patient is a critical parameter thatdirectly relates to risk factors for stroke and/or congestive heartfailure, especially for patients with high CHA2DS2-VASc scores. In Table8, there was a 76.7% drop in percent time in AFib for patients using 200mg budiodarone twice a day, which further drops to 90% for patientsusing 600 mg budiodarone twice a day, and even further drops to 94.8%for patients using 800 mg budiodarone twice a day.

Example 7—Measurement of Longest Episodes of AFib During the Twelve WeekPeriod

This example is a clinical trial evaluation of 6 patients treated withdifferent doses of budiodarone each for a two-week period to determinethe longest duration episode of AFib experienced at each dose. In thisexample, the patients' heart rhythms were continuously monitored over atwelve-week period with a pacemaker. The different doses and results ofthis evaluation are provided in Table 9 below:

TABLE 9 2 Weeks Subject 1 Subject 2 Subject 3 Subject 4 Subject 5Subject 6 Total Baseline 13 hrs  16 hrs  50 hrs  5 hrs   8 hrs 35 hrs127 hrs 200 mg 5 hrs 6 hrs 7 hrs 0 hrs   3 hrs  6 hrs  21 hrs bid 400 mg8 hrs 13 hrs  — 2 hrs   2 hrs 10 hrs  33 hrs bid 600 mg 7 hrs 0 hrs — 2hrs 0.8 hrs  0 hrs  7.8 hrs bid 800 mg 3 hrs 5 hrs — 1 hr  1.6 hrs  3hrs 13.6 hrs  bid Washout 105 hrs  12 hrs  8 hrs 16 hrs    2 hrs 18 hrs161 hrs

The above results evidence the variability of long duration AFib (whenequal to or greater than 5 hours) in a patient treated with differentdoses of budiodarone. In Subjects 4 and 5, treatment with just 200 mgbudiodarone twice a day was sufficient to eliminate all episodes of longduration AFib (>5 hrs) in these patients. However, Subject 1 required800 mg bid budiodarone to eliminate all episodes of long duration AFib(>5 hrs) whereas Subject 6 required 600 mg budiodarone bid to eliminateall episodes of budiodarone. This data establishes how long termmonitoring of a patient coupled with a dose adjustment of budiodarone isrequired to properly treat patients with paroxysmal or persistent AFibevidencing episodes of long duration AFib.

The results of Examples 2 to 7 establish that the use of an appropriatedose of budiodarone coupled with monitoring heart rhythms of treatedpatients allows for a reduction of all episodes of long duration AFib ofgreater than 5 hours coupled with a reduction in the overall AFibburden. This latter result evidences that a patient's progression fromparoxysmal AFib to persistent AFib or from persistent AFib to permanentAFib can be reduced or prevented.

The administration of budiodarone according to the present method may beconducted using a pharmaceutical composition comprising from about 1% to99% of budiodarone and the remainder being a pharmaceutically acceptableexcipient, such as corn starch, cellulose, stearic acid, water, or othercomponents. The pharmaceutical composition can be formulated into anyform which, by way of example, only, may include one or more of atablet, a capsule, a powder, and/or another formulation for oraladministration; a parenteral administration, such as a solution suitablefor one or more of intravenous administration, intramuscularadministration, etc.; a suppository and/or enema; cutaneous and/ortransdermal preparations, etc.

Example 8—Programming the Wearable

In an embodiment, the wearable may be programmable (e.g., by theclinician, the patient, and/or remotely, such as by the central analysiscenter). The wearable may be programmed to capture the patient's heartrhythm data. The data so generated can be interrogated and/or analyzedby the CPU on the wearable and/or can be transmitted to another devicefor interrogation and/or analysis. One example of programming of thewearable may enable the use of the wearable for monitoring the patient'sheart rhythm and relaying the data directly and/or indirectly to, e.g.,a clinician as follows.

A. A USER INTERFACE: Step functions for programming AFib monitoringsystem involving the wearable and relying on information through anetwork to the attending clinician.

B. The data collected is in a readable display for the clinician andother authorized individuals to access.

C. The readable display should be made available to the authorizedclinician at all times, and only the authorized clinician should beauthorized to save data and/or reset the monitoring system after goingthrough one or more of Steps 1-15 below.

D. Drug exposure, dose, and/or any other medicaments taken by thepatient can be retrieved as needed by the clinician from a patient'smedical records, e.g., by integrating the monitoring system with thepatient's medical records (e.g., electronic medical records).

E. Steps 1 to 14 are the only manual entry required, but step 14 isoptimal and can be overridden by the clinician simply pushing ManualReset Step 15.

F. All data may be saved after review by the attending clinician, whomay also be authorized to program integration of prior observationperiods (Step 17), whether on or off a pharmaceutical to treat AFibincluding budiodarone.

G. The system is user friendly, the attending clinician only needs to do4 things each time: 1) enter patient or code to access data, 2) reviewdata display, 3) enter dose of budiodarone in Step 14 if they wish, then4) Push Manual Reset and Store Data.

H. The attending clinician has access to the stored data and integratesobservation periods to compare AFib characteristics on different dosesof budiodarone or off-drug (Step 17).

Each of the steps are set forth in Table 10 below:

TABLE 10 Units Step Function or Desired Output Displayed FunctionRecorded 1 Patient Name or Code Characters Uncharged 2 Patient Age YearsUnchanged 3 Observation Period Numbers 1-1000  3a Observation IntervalWeeks Minimum reset at least 1 week and preferably at least 2 weeks 4 %Time in AFib % 0-100% 5 Longest Episode Hours Continuous variable 6Number of episodes > 24 hrs Number Continuous variable 7 Duration ofepisodes > 24 hrs Hours Continuous variable 8 Number of episodes > 5 hrsNumber Continuous variable 9 Duration of episodes > 5 hrs HoursContinuous variable 10  Number of episodes > 1 hr Number Continuousvariable 11  Duration of episodes > 1 hr Hours Continuous variable 12 Number of episodes > 0.1 hr Number Continuous variable 13  Duration ofepisodes > 0.1 hr Hours Continuous variable 14  Dose of Pharmaceuticalmg/day Optional Entry by (e.g., Budiodarone) Clinician 15  Push ManualReset and Save — Once 16  Entry Accessed in Saved Data All AboveUnlimited 17  Integration of Saved Data Periods #'s Unlimited

Each of Steps 4-13 may be included or excluded in the programming of thewearable (e.g., at the discretion of the clinician), provided that atleast one of these steps is included. In one embodiment, Steps 4-7 maybe performed, and the corresponding data collected, and one or more ofSteps 8-13 may be excluded. In another embodiment, Steps 4, 5, 8, and 9may be included, and Steps 5, 6, and 10-13 may be excluded. In anotherembodiment, Steps 4, 5, 10, and 11 may be included, and steps 6, 7, 8,9, 12, and 13 may be excluded. In yet another embodiment, Steps 4, 5,12, and 13 may be included and Steps 6-11 may be excluded.

In still another embodiment, the attending clinician may program thewearable according to one or more of Steps 4-13.

EMBODIMENTS

Provided below are certain embodiments.

Embodiment I-1. A method to assess whether a patient with eitherparoxysmal or persistent atrial fibrillation (AFib) qualifies for abudiodarone therapy, the method comprising:

-   -   a) selecting a patient afflicted with paroxysmal or persistent        AFib;    -   b) fitting said patient with a wearable, wherein said wearable        comprises:        -   i) at least one of an electrode or an optical sensor,            wherein the at least one of the electrode or the optical            sensor is configured to, when the wearable is fitted on the            patient, continuously or semi-continuously monitor a heart            rhythm of the patient;        -   ii) a first computing device configured to collect and store            heart rhythm data based on the monitored heart rhythm; and        -   iii) a transmission component configured to transmit data            based on the heart rhythm data in the first computing device            to a second computing device accessible by a clinician;    -   c) causing transmission of the data to the second computing        device, wherein the data indicates at least one of a presence of        a long duration episode of AFib, an absence of a long duration        episode of AFib, a number of long duration episodes of AFib, and        optionally an extent of AFib burden; and    -   d) qualifying said patient for budiodarone therapy based on a        determination that the data satisfies at least one of a        threshold number of long duration episodes of AFib and/or a        threshold AFib burden.

Embodiment I-2. The method of embodiment I-1, wherein the firstcomputing device is configured to determine the data based on the heartrhythm data by evaluating the stored heart rhythm data to determine thepresence of a long duration episode of AFib and the number of longduration episodes of AFib.

Embodiment I-3. The method of embodiment I-2, wherein said evaluating iscontinuous.

Embodiment I-4. The method of any of embodiment I-2 or embodiment I-3,wherein said evaluating is also, or alternatively, semi-continuous.

Embodiment I-5. The method of any of embodiments I-1 to I-4, wherein thefirst computing device is programmed to, based on the data, alert atleast one of the clinician or the patient of a detected long-durationepisode of AFib that places the patient at risk of stroke.

Embodiment I-6. The method according to any of embodiments I-1 to I-5,wherein the qualifying said patient for budiodarone therapy comprisesdetermining, based on the data, that the patient meets at least one ofthe following criteria:

-   -   a) at least one AFib episode of at least 5 hours duration in a        30-day period or at least two episodes at least 1 hour in        duration in a 30-day period coupled with an AFib burden at least        2.5% during the 30-day period;    -   b) at least one AFib episode of at least 5 hours duration in a        30-day period or at least 2 episodes at least one hour in        duration in a 30-day period coupled with an AFib burden at least        5% during the 30-day period;    -   c) at least one AFib episode of at least 5 hours duration in a        30-day period coupled with an AFib burden at least 2.5% during        the 30-day period;    -   d) at least one AFib episode of at least 5 hours duration in a        30-day period coupled with an AFib burden at least 5% during the        30-day period;    -   e) at least two AFib episodes of at least 1 hour in duration in        a 30-day period coupled with an AFib burden at least 2.5% during        the 30-day period; or    -   f) at least two AFib episodes of at least 1 hour duration in a        30-day period coupled with an AFib burden at least 5% during the        30-day period.

Embodiment I-7. The method according to any of embodiments I-1 to I-6,wherein the wearable is one or more of a patch, a watch, a wristband, astrap, a ring, or a device that adheres to a body when fitted, andwherein the wearable is configured to measure the heart rhythm andtransmit the heart rhythm data directly or indirectly to the secondcomputing device.

Embodiment I-8. The method according to any of embodiments I-1 to I-7,wherein the patient is refractory to one or more other methods oftreating AFib.

Embodiment II-1. A method of treating a patient diagnosed with eitherparoxysmal or persistent atrial fibrillation (AFib), the methodcomprising:

administering budiodarone to the patient;

wherein the patient was identified for budiodarone treatment based on:

a to be identified patient being fit with a wearable, wherein saidwearable comprises:

at least one of an electrode or an optical sensor, wherein the at leastone of the electrode or the optical sensor is configured to, when thewearable is fitted on said to be identified patient, continuously orsemi-continuously monitors a heart rhythm of said to be identifiedpatient;

a first computing device configured to collect and store heart rhythmdata based on the monitored heart rhythm of said to be identifiedpatient; and

a transmission component configured to transmit data based on the heartrhythm data of said to be identified patient in the first computingdevice to a second computing device accessible by a clinician;

the data of said to be identified patient being transmitted to thesecond computing device, wherein the data indicated at least one of apresence of a long duration episode of AFib, an absence of any longduration episode of AFib, a number of long duration episodes of AFib,and optionally an extent of AFib burden; and

a determination being made that the data satisfied at least one of athreshold number of long duration episodes of AFib and/or a thresholdAFib burden; and

wherein said patient identified for budiodarone treatment is determinedto have budiodarone responsive AFib.

Embodiment II-2. The method of embodiment II-1, wherein the patientidentified for budiodarone is refractory to one or more other methods oftreating AFib.

Embodiment III-1. A method to assess if a qualified patient onbudiodarone therapy should be dose adjusted for or disqualified from abudiodarone therapy, the method comprising:

-   -   a) selecting the qualified patient; wherein the qualified        patient is:        -   on budiodarone therapy comprising treatment with a dose of            budiodarone or a pharmaceutical composition comprising            budiodarone; and fitted with a wearable, wherein said            wearable comprises:        -   i) at least one of an electrode or optical sensor, wherein            the at least one of the electrode or the optical sensor is            configured to, when the wearable is fitted, continuously or            semi-continuously monitor a heart rhythm of the qualified            patient;        -   ii) a first computing device configured to collect and store            heart rhythm data based on the monitored heart rhythm; and        -   iii) a transmission component configured to transmit data            based on the heart rhythm data in the first computing device            to a second computing device accessible by a clinician;    -   c) causing collection and transmission of the heart rhythm data        to the second computing device, wherein the second computing        device is configured to evaluate the heart rhythm data for a        presence and a number of long duration episodes of AFib and an        extent of AFib burden;    -   d) optionally adjusting the dose of budiodarone to assess an        appropriate dose for that patient; and    -   e) assessing whether the collected heart rhythm data that the        patient is responsive, is partially responsive, or is not        responsive to budiodarone therapy;

wherein said therapy is maintained for responsive patients, adjusted forpartially responsive patients, and further wherein said therapy isterminated for non-responsive patients.

Embodiment III-2. The method of embodiment III-1, wherein said dose ofbudiodarone is at least about 200 mg twice a day.

Embodiment III-3. The method according to any of embodiments III-1 toIII-2, wherein said dose of budiodarone is from about 200 mg twice a dayto about 800 mg twice a day.

Embodiment III-4. The method of embodiment III-3, wherein said dose ofbudiodarone is selected from about 200 mg twice a day, about 400 mgtwice a day, 600 mg twice a day, and about 800 mg twice a day.

Embodiment III-5. The method according to any of embodiments III-1 toIII-4, wherein budiodarone is administered as a pharmaceuticalcomposition.

Embodiment III-6. The method according to any of embodiments III-1 toIII-5, wherein said monitoring with the wearable is maintained for theresponsive patients to confirm that said patients remain responsive.

Embodiment III-7. The method of embodiment III-6, wherein said patientswho are initially responsive to budiodarone but who later becomenon-responsive are dose adjusted with budiodarone provided that if saiddose adjustment fails to restore the patient budiodarone responsive, thepatient is removed from treatment with budiodarone.

Embodiment III-8. The method according to any of embodiments III-1 toIII-7, wherein said responsive patients are placed in a registry thatidentifies those patients as eligible for treatment with budiodaronewherein a listing in the registry is a requirement for receivingbudiodarone.

Embodiment III-9. The method according to any of embodiments III-1 toIII-8, wherein the data generated by the wearable is transmitteddirectly or indirectly to a clinician who can assess a presence or anabsence of long duration AFib and optionally the extent of AFib burdento the patient.

Embodiment III-10. The method of embodiment III-9, wherein said data isinitially transmitted to a remote laboratory where a qualified healthcare professional analyzes the data.

Embodiment III-11. The method of embodiment III-10, wherein saidqualified health care professional confirms that the patient is eligiblefor treatment with budiodarone and provides, to an attendinginformation, information indicating:

that said professional has confirmed that the patient is eligible; and

one or more of the data or the analysis made by said professional.

Embodiment III-12. The method according to any of embodiments III-10 toIII-11 wherein said qualified health care professional determineswhether a patient responsive to treatment with a given dose ofbudiodarone remains responsive; and

if said qualified health care professional determines that said patientis now non-responsive, said professional provides said determination toan attending clinician, with one or more of:

-   -   a recommendation to dose adjust the patient to restore the        patient's responsiveness; or

a recommendation to terminate the patient's treatment with budiodaroneif said now non-responsive patient is being treated with a maximumprescribed dose.

Embodiment III-13. The method according to any of embodiments III-1 toIII-12, wherein the assessing the collected heart rhythm data comprisesassessing the collected heart rhythm data that was collected beginningat least 3 days after either budiodarone administration was initiated ordose adjustment of budiodarone was initiated.

Embodiment III-14. The method according to any of embodiments III-1 toIII-13, wherein the assessing the collected heart rhythm data comprisesassessing the collected heart rhythm data that was collected beginningat least 14 days after either budiodarone administration is initiated ordose adjustment of budiodarone is initiated.

Embodiment IV-1. A method for reducing a risk of a patient progressingfrom paroxysmal AFib to persistent AFib or from persistent AFib topermanent AFib, which method comprises:

identifying a patient with either paroxysmal or persistent AFib having aAFib burden of at least 2.5% coupled with at least one episode of longduration AFib over a 4-week period; administering budiodarone to saidpatient at a dose;

monitoring efficacy of said administration and optionally adjusting thedose as needed to achieve a reduction in either or both of AFib burdenand long duration AFib, whereupon the risk of progression fromparoxysmal AFib to persistent AFib or from persistent AFib to permanentAFib is reduced by said dose adjustment; and

maintaining said patient monitoring to confirm continued efficacy ofbudiodarone.

Embodiment IV-2. The method of embodiment IV-1, wherein the method also,or alternatively, comprises one or more of:

assessing whether the patient qualifies for a budiodarone therapyaccording to any of embodiments I-1 to I-8;

treating the patient according to any of embodiments II-1 to II-2; orassessing whether the patient should be dose adjusted for ordisqualified from budiodarone therapy according to any of embodimentsIII-1 to III-14.

Embodiment V-1. A method for reducing a risk of heart failure in apatient diagnosed with paroxysmal AFib or persistent AFib, which methodcomprises:

identifying a patient with either paroxysmal or persistent AFib havingan AFib burden of at least 2.5% coupled with at least one episode oflong duration AFib over a 4-week period; administering budiodarone tosaid patient at a dose;

monitoring efficacy of said dose administration and optionally adjustingthe dose to achieve a reduction in either or both of AFib burden andlong duration AFib, whereupon the risk of heart failure in said patientis reduced; and maintaining said patient monitoring to confirm continuedefficacy of budiodarone.

Embodiment V-2. The method of embodiment V-1, wherein the method also,or alternatively, comprises one or more of:

assessing whether the patient qualifies for a budiodarone therapyaccording to any of embodiments I-1 to I-8;

treating the patient according to any one of embodiments II-1 to II-2;or assessing whether the patient should be dose adjusted for ordisqualified from budiodarone therapy according to any of embodimentsIII-1 to III-14.

Embodiment VI-1. A method for reducing a risk of stroke in a patientdiagnosed with paroxysmal AFib or persistent AFib, which methodcomprises:

identifying a patient with either paroxysmal or persistent AFib havingan AFib burden of at least 2.5% coupled with at least one episode oflong duration AFib over a 4-week period; administering budiodarone tosaid patient at a dose;

monitoring efficacy of said administration and optionally adjusting thedose as needed to achieve a reduction in either or both of AFib burdenand long duration AFib whereupon the risk of stroke in said patient isreduced; and

maintaining said patient monitoring to confirm continued efficacy ofbudiodarone.

Embodiment VI-2. The method of embodiment VI-1, wherein the method also,or alternatively, comprises one or more of:

assessing whether the patient qualifies for a budiodarone therapyaccording to any of embodiments I-1 to I-8;

treating the patient according to any one of embodiments II-1 to II-2;or

assessing whether the patient should be dose adjusted for ordisqualified from budiodarone therapy according to any of embodimentsIII-1 to III-15.

Embodiment VII-1. A method to treat a patient with paroxysmal orpersistent AFib, wherein said patient is refractory to one or more priormethods to treat AFib, which method comprises:

-   -   a) selecting a patient who is refractory to the one or more        prior methods to treat AFib;    -   b) identifying a number of episodes of long duration AFib and an        extent of AFib burden in the patient;    -   c) qualifying the patient for a budiodarone treatment at a        dosage based on the number of episodes of long duration AFib and        the extent of AFib burden;    -   d) fitting said patient with a wearable, wherein said wearable        comprises:        -   i) at least one of an electrode or an optical sensor,            wherein said at least one of the electrode or the optical            sensor, when the wearable is fitted on the patient,            continuously or semi-continuously monitor a heart rhythm of            the patient;        -   ii) a first computing device configured to collect and store            heart rhythm data based on the monitored heart rhythm of the            patient; and        -   iii) a transmission component configured to be able to            transmit data based on the heart rhythm data in the first            computing device to a second computing device accessible by            a clinician;    -   e) causing collection and transmission of the data based on the        heart rhythm data to the second computing device, where the data        is evaluated for a presence and number of long duration episodes        of AFib and the extent of AFib burden;    -   f) optionally adjusting dosing of budiodarone for the patient to        assess an appropriate dose for the patient; and    -   g) assessing whether the collected heart rhythm data evidence        that the patient is responsive or is non-responsive to        budiodarone therapy;

wherein said therapy is maintained for responsive patients and whereinsaid therapy is terminated for non-responsive patients.

Embodiment VII-2. The method of embodiment VII-1, wherein the methodalso, or alternatively, comprises one or more of:

assessing whether the patient qualifies for a budiodarone therapyaccording to any of embodiments I-1 to I-8;

treating the patient according to any one of embodiments II-1 to II-2;or

assessing whether the patient should be dose adjusted for ordisqualified from budiodarone therapy according to any of embodimentsIII-1 to III-15.

Embodiment VIII-1. A method for reducing a risk that a patient withparoxysmal AFib will transition into persistent AFib, which methodcomprises:

identifying a patient with paroxysmal AFib having an AFib burden of atleast 2.5% coupled with at least one episode of long duration AFib overa 4-week period;

administering budiodarone to said patient at a dose;

monitoring efficacy of said administration and optionally adjusting thedose as needed to achieve a reduction in either or both of AFib burdenand long duration AFib whereupon the risk of said transition in saidpatient is reduced; and

maintaining said monitoring the patient to confirm continued efficacy ofbudiodarone.

Embodiment VIII-2. The method of embodiment VIII-1, wherein the methodalso, or alternatively, comprises one or more of:

assessing whether the patient qualifies for a budiodarone therapyaccording to any of embodiments I-1 to I-8;

treating the patient according to any one of embodiments II-1 to II-2;or

assessing whether the patient should be dose adjusted for ordisqualified from budiodarone therapy according to any of embodimentsIII-1 to III-15.

Embodiment IX-1. A method for reducing a risk that a patient withpersistent AFib will transition into permanent AFib, which methodcomprises:

identifying a patient with persistent AFib having an AFib burden of atleast 2.5% coupled with at least one episode of long duration AFib overa 4-week period;

administering budiodarone to said patient at a dose;

monitoring efficacy of said administration and optionally adjusting thedose as needed to achieve a reduction in either or both of AFib burdenand long duration AFib, whereupon the risk of said transition in saidpatient is reduced; and

maintaining said monitoring the patient to confirm continued efficacy ofbudiodarone.

Embodiment IX-2. The method according to embodiment IX-1, also, oralternatively, comprising one or more of:

assessing whether the patient qualifies for a budiodarone therapyaccording to any of embodiments I-1 to I-8;

treating the patient according to any one of embodiments II-1 to II-2;or

assessing whether the patient should be dose adjusted for ordisqualified from budiodarone therapy according to any of embodimentsIII-1 to III-15.

What is claimed is:
 1. A method to determine whether a patient sufferingfrom paroxysmal or persistent atrial fibrillation (AFib) and qualifiedfor treatment with budiodarone therapy is responsive to said budiodaronetherapy or should be disqualified from said budiodarone therapy, themethod comprising: a) administering to said qualified patient a firstdose of budiodarone of at least 200 mg twice a day, wherein saidqualified patient was qualified for budiodarone therapy based onexperiencing, over a qualification period in which said qualifiedpatient did not receive budiodarone therapy, one or more of: a baselinenumber of episodes of long duration AFib satisfying a threshold numberof episodes of long duration AFib, or a baseline AFib burden of thepatient satisfying a threshold AFib burden; b) monitoring heart rhythmdata of said qualified patient being administered said first dose ofbudiodarone, wherein, at least about 3 days after initiation ofadministration of said first dose, said monitored heart rhythm data isevaluated for one or more of: a number of episodes of long durationAFib, a length of episodes of long duration AFib, or an extent of AFibburden; c) assessing if the first dose of budiodarone is effective intreating AFib, wherein said first dose of budiodarone is assessed aseffective if said first dose reduces, for said qualified patient andrelative to baseline data collected during said qualification period,one or more of: the number of episodes of long duration AFib; the lengthof episodes of long duration AFib; or the AFib burden; d) if said firstdose is assessed as not effective, adjusting said first dose ofbudiodarone one or more times, provided that said adjusted dose does notexceed 800 mg twice a day, and assessing whether said adjusted dose ofbudiodarone is effective, provided that if an effective dose isassessed, dose adjustment is terminated; and e) if, at any time, it isdetermined that no dose of budiodarone equal to or less than 800 mgtwice a day is effective for said qualified patient, determining thatsaid qualified patient should be disqualified from budiodarone therapyand terminating budiodarone therapy for said disqualified patient. 2.The method of claim 1, wherein said qualified patient is refractory toone or more other methods of treating AFib.
 3. The method of claim 1,wherein said qualification period is at least about 14 days and saidqualified patient was qualified for budiodarone therapy based onexperiencing, over the qualification period, one or more of: a) at leastone AFib episode of at least 5 hours duration or at least two AFibepisodes of at least 1 hour duration coupled with the AFib burden of atleast 2.5%; b) at least one AFib episode of at least 5 hours duration orat least 2 AFib episodes of at least one hour duration coupled with theAFib burden of at least 5%; c) at least one AFib episode of at least 5hours duration coupled with the AFib burden of at least 2.5%; d) atleast one AFib episode of at least 5 hours duration coupled with theAFib burden of at least 5%; e) at least two AFib episodes of at least 1hour duration coupled with the AFib burden of at least 2.5%; or f) atleast two AFib episodes of at least 1 hour duration coupled with theAFib burden of at least 5%.
 4. The method of claim 1, wherein the heartrhythm data is collected via a wearable comprising one or more of apatch, a watch, a wristband, a strap, a ring, or a device that adheresto a body.
 5. The method of claim 4, wherein the at least one of anelectrode or an optical sensor continuously monitors the heart rhythm ofsaid qualified patient.
 6. The method of claim 4, wherein the at leastone of an electrode or an optical sensor semi-continuously monitors theheart rhythm data of said qualified patient.
 7. The method of claim 4,wherein the wearable is programmed to, based on the heart rhythm data,alert at least one of a clinician or said qualified patient of adetected episode of long duration AFib that places said qualifiedpatient at risk of stroke.
 8. The method of claim 1, further comprising,if said effective dose is assessed for said qualified patient,monitoring said qualified patient on budiodarone therapy at saideffective dose to confirm that said effective dose remains effective forsaid qualified patient.
 9. The method of claim 8, further comprising, ifsaid monitoring indicates that said effective dose is no longereffective for said qualified patient: adjusting said dose ofbudiodarone, provided that said adjusted dose does not exceed 800 mgtwice a day, and assessing whether said adjusted dose of budiodarone iseffective; or if adjusting the effective dose would result in anadjusted dose that exceeds 800 mg twice a day, determining that saidqualified patient is disqualified for budiodarone therapy andterminating budiodarone therapy for said disqualified patient.
 10. Themethod of claim 1, wherein it is determined that no dose of budiodaroneis effective for said qualified patient based on: said effective dosefor said qualified patient being assessed as not effective, and nosubsequently administered dose equal to or below 800 mg twice a daybeing assessed as effective.
 11. The method of claim 1, wherein a doseis assessed to be effective if it reduces, in said qualified patientwhen administered said dose of budiodarone relative to when notadministered budiodarone, the number of episodes of long duration AFiblasting at least 5 hours by at least 85% over an at least 2 week period.12. The method of claim 1, wherein a said effective dose is assessed tobe effective if it reduces, in said qualified patient when administeredsaid effective dose of budiodarone relative to when not administeredbudiodarone, the number of episodes of long duration AFib lasting atleast 1 hours by at least 66% over an at least 2 week period.
 13. Amethod to determine whether a patient suffering from paroxysmal orpersistent atrial fibrillation (AFib) and qualified for treatment withbudiodarone therapy is responsive to said budiodarone therapy or shouldbe disqualified from said budiodarone therapy, the method comprising,the method comprising: a) administering to said qualified patient afirst dose of budiodarone of at least 200 mg twice a day, wherein saidqualified patient was qualified for budiodarone therapy based onexperiencing, over qualification period in which said qualified patientdid not receive budiodarone therapy, one or more of: a baseline numberof episodes of long duration AFib satisfying a threshold number ofepisodes of long duration AFib, or a baseline AFib burden of the patientsatisfying a threshold AFib burden; b) monitoring heart rhythm data ofsaid qualified patient being administered said first dose ofbudiodarone, wherein, at least about 3 days after initiation ofadministration of said first dose, said monitored heart rhythm isevaluated for one or more of: a number of episodes of long durationAFib, a length of episodes of long duration AFib, or an extent of AFibburden; c) assessing if the first dose of budiodarone is effective intreating AFib, wherein said first dose of budiodarone is assessed aseffective if said first dose eliminates, for said qualified patientwhile being administered said first dose, episodes of long durationAFib; d) if said first dose is assessed as not effective, adjusting saidfirst dose of budiodarone one or more times, provided that said adjusteddose does not exceed 800 mg twice a day, and assessing whether saidadjusted dose of budiodarone is effective, provided that if an effectivedose is assessed, dose adjustment is terminated; and e) if, at any time,it is determined that no dose of budiodarone equal to or less than 800mg twice a day is effective for said qualified patient, determining thatsaid qualified patient should be disqualified from budiodarone therapyand terminating budiodarone therapy for said disqualified patient. 14.The method of claim 13, wherein flail said effective dose is assessed tobe effective for said qualified patient if it eliminates episodes oflong duration AFib lasting at least 1 hour.
 15. The method of claim 4,wherein the wearable is configured to measure the heart rhythm data andto transmit the heart rhythm data directly or indirectly to a computingdevice.
 16. The method of claim 1, wherein the monitoring the heartrhythm data is performed continuously or semi-continuously, and whereinthe heart rhythm data is evaluated periodically with a period of atleast about three days.
 17. The method of claim 1, wherein flail saideffective dose of budiodarone is assessed as effective if said effectivedose reduces, for said qualified patient and relative to baseline datacollected during said qualification period, one or more of the followingby at least 10%: the number of long duration episodes of AFib lastingover 24 hours; the number of long duration episodes of AFib lasting over5 hours; the number of long duration episodes of AFib lasting over 1hour; or the AFib burden.
 18. The method of claim 1, wherein said firstdose of budiodarone is one of: about 200 mg twice a day; about 400 mgtwice a day; about 600 mg twice a day; or about 800 mg twice a day. 19.A method to determine whether a patient suffering from paroxysmal orpersistent atrial fibrillation (AFib) and qualified for treatment withbudiodarone therapy is responsive to said budiodarone therapy or shouldbe disqualified from said budiodarone therapy, the method comprising: a)administering to said qualified patient a first dose of budiodarone ofat least 200 mg twice a day, wherein said qualified patient wasqualified for budiodarone therapy based on experiencing, over aqualification period in which said qualified patient did not receivebudiodarone therapy, one or more of: a baseline number of episodes oflong duration AFib satisfying a threshold number of episodes of longduration AFib, or a baseline AFib burden of the patient satisfying athreshold AFib burden; b) monitoring heart rhythm data of said qualifiedpatient being administered said first dose of budiodarone, wherein, atleast about 3 days after initiation of administration of said firstdose, said monitored heart rhythm data is evaluated for one or more of:a number of episodes of long duration AFib, a length of episodes of longduration AFib, or an extent of AFib burden; c) assessing if the firstdose of budiodarone is effective in treating AFib, wherein said firstdose of budiodarone is assessed as effective if said first dose reduces,for said qualified patient and relative to baseline data collectedduring said qualification period, one or more of: the number of episodesof long duration AFib; the length of episodes of long duration AFib; orthe AFib burden; d) if said first dose is assessed as not effective,adjusting said first dose of budiodarone one or more times, providedthat said adjusted dose does not exceed 800 mg twice a day, andassessing whether said adjusted dose of budiodarone is effective,provided that if an effective dose is assessed, dose adjustment isterminated; e) if said effective dose is assessed for said qualifiedpatient, monitoring said qualified patient on budiodarone therapy atsaid effective dose to confirm that said effective dose remainseffective for said qualified patient; and f) if, at any time, it isdetermined that no dose of budiodarone equal to or less than 800 mgtwice a day is effective for said qualified patient, determining thatsaid qualified patient should be disqualified from budiodarone therapyand terminating budiodarone therapy for said disqualified patient.
 20. Amethod to determine whether a patient suffering from paroxysmal orpersistent atrial fibrillation (AFib) and qualified for treatment withbudiodarone therapy is responsive to or should be disqualified from saidbudiodarone therapy, wherein qualification is based on baseline data forthe severity of the AFib in said patient indicating that, over aqualification period in which said patient did not receive budiodaronetherapy, the patient has had one or more episodes of long duration AFibextending for at least 1 hour or has a maximal AFib burden of at least 5hours, the method comprising: a) administering to said qualified patienta first dose of budiodarone of at least 200 mg twice a day; b)monitoring heart rhythm data of said qualified patient beingadministered said first dose of budiodarone, wherein said monitoredheart rhythm data is evaluated at least 3 days after initiation ofbudiodarone therapy for one or more of: a number of episodes of longduration AFib, a length of episodes of long duration AFib, or an extentof AFib burden; c) assessing if the first dose of budiodarone iseffective in treating AFib, wherein said first dose of budiodarone isassessed as effective if said first dose reduces, by at least 10% ascompared to the baseline data, or eliminates, for said qualifiedpatient, one or more of: the number of episodes of long duration AFib;the length of episodes of long duration AFib; or the AFib burden; d) ifsaid first dose is assessed as not effective, adjusting said first doseof budiodarone one or more times, provided that said adjusted dose doesnot exceed 800 mg twice a day, and assessing whether said adjusted doseof budiodarone is effective as provided above, provided that if aneffective dose is assessed, dose adjustment is terminated; and e) if, atany time, it is determined that no dose of budiodarone, equal to or lessthan 800 mg twice a day, administered to said patient is effective, thendisqualifying said patient from budiodarone therapy.
 21. The method ofclaim 20, wherein said qualified patient is refractory to one or moreother methods of treating AFib.
 22. The method of claim 20, wherein thequalification period is at least about 14 days and said qualifiedpatient was qualified for budiodarone therapy based on experiencing,over the qualification period, one or more of: a) at least one AFibepisode of at least 5 hours duration or at least two AFib episodes of atleast 1 hour duration coupled with the AFib burden of at least 2.5%; b)at least one AFib episode of at least 5 hours duration or at least 2AFib episodes of at least one hour duration coupled with the AFib burdenof at least 5%; c) at least one AFib episode of at least 5 hoursduration coupled with the AFib burden of at least 2.5%; d) at least oneAFib episode of at least 5 hours duration coupled with the AFib burdenof at least 5%; e) at least two AFib episodes of at least 1 hourduration coupled with the AFib burden of at least 2.5%; or f) at leasttwo AFib episodes of at least 1 hour duration coupled with the AFibburden of at least 5%.
 23. The method of claim 20, wherein the heartrhythm data is collected via a wearable comprising one or more of apatch, a watch, a wristband, a strap, a ring, or a device that adheresto a body.
 24. The method of claim 23, wherein the at least one of anelectrode or an optical sensor continuously monitors the heart rhythm ofsaid qualified patient.
 25. The method of claim 23, wherein the at leastone of an electrode or an optical sensor semi-continuously monitors theheart rhythm data of said qualified patient.
 26. The method of claim 23,wherein the wearable is programmed to, based on the heart rhythm data,alert at least one of a clinician or said qualified patient of adetected episode of long duration AFib that places said qualifiedpatient at risk of stroke.
 27. The method of claim 23, wherein thewearable is configured to measure the heart rhythm data and to transmitthe heart rhythm data directly or indirectly to a computing device. 28.The method of claim 20, wherein the monitoring the heart rhythm data isperformed continuously or semi-continuously, and wherein the heartrhythm data is evaluated periodically with a period of at least abouttwo weeks.
 29. The method of claim 20, further comprising, if saideffective dose is assessed for said qualified patient, monitoring saidqualified patient on budiodarone therapy at said effective dose toconfirm that said effective dose remains effective for said qualifiedpatient.
 30. The method of claim 29, further comprising, if saidmonitoring indicates that said effective dose is no longer effective forsaid qualified patient: adjusting said formerly effective dose ofbudiodarone, provided that said adjusted formerly effective dose doesnot exceed 800 mg twice a day, and assessing whether said adjustedformerly effective dose of budiodarone is effective; or if adjustingsaid formerly effective dose would result in an adjusted dose thatexceeds 800 mg twice a day, determining that said qualified patientshould be disqualified for budiodarone therapy and terminatingbudiodarone therapy for said disqualified patient.
 31. The method ofclaim 20, wherein it is determined that no dose of budiodarone iseffective for said qualified patient based on: said effective dose forsaid qualified patient being assessed as not effective, and nosubsequently administered dose equal to or below 800 mg twice a daybeing assessed as effective.
 32. The method of claim 20, wherein saidfirst dose or said adjusted dose is assessed to be effective if itreduces, in said qualified patient when administered said first dose orsaid adjusted dose of budiodarone relative to when not administeredbudiodarone, the number of episodes of long duration episodes AFiblasting at least 5 hours by at least 85% over an at least 2 week period.33. The method of claim 20, wherein said first dose or said adjusteddose is assessed to be effective if it reduces, in said qualifiedpatient when administered said first dose or said adjusted dose ofbudiodarone relative to when not administered budiodarone, the number ofepisodes of long duration AFib lasting at least 1 hours by at least 66%over an at least 2 week period.
 34. The method of claim 20, wherein saideffective dose of budiodarone is assessed to be effective for saidqualified patient if it eliminates the episodes of long duration AFiblasting at least 1 hour.
 35. The method of claim 20, wherein saideffective dose of budiodarone is assessed as effective if said dosereduces, for said qualified patient and relative to the baseline datacollected during said qualification period, one or more of the followingby at least 10%: the number of episodes of long duration AFib lastingover 24 hours; the number of episodes of long duration AFib lasting over5 hours; or the number of episodes of long duration AFib lasting over 1hour; or the AFib burden.
 36. The method of claim 20, wherein said firstdose of budiodarone is one of: about 200 mg twice a day; about 400 mgtwice a day; about 600 mg twice a day; or about 800 mg twice a day. 37.A method to determine whether a patient suffering from paroxysmal orpersistent atrial fibrillation (AFib) and qualified for treatment withbudiodarone therapy is responsive to said budiodarone therapy or shouldbe disqualified from said budiodarone therapy, the method comprising: a)administering to said qualified patient a first dose of budiodarone ofat least 400 mg twice a day, wherein said qualified patient wasqualified for budiodarone therapy based on experiencing, over aqualification period in which said qualified patient did not receivebudiodarone therapy, one or more of: a baseline number of episodes oflong duration AFib satisfying a threshold number of episodes of longduration AFib, or a baseline AFib burden of the patient satisfying athreshold AFib burden; b) monitoring heart rhythm data of said qualifiedpatient being administered said first dose of budiodarone, wherein, atleast about 3 days after initiation of administration of said firstdose, said monitored heart rhythm data is evaluated for one or more of:a number of episodes of long duration AFib, a length of episodes of longduration AFib, or an extent of AFib burden; c) assessing if the firstdose of budiodarone is effective in treating AFib, wherein said firstdose of budiodarone is assessed as effective if said first dose reduces,for said qualified patient and relative to baseline data collectedduring said qualification period, one or more of: the number of episodesof long duration AFib; the length of episodes of long duration AFib; orthe AFib burden; d) if said first dose is assessed as not effective,adjusting said first dose of budiodarone one or more times, providedthat said adjusted dose does not exceed 800 mg twice a day, andassessing whether said adjusted dose of budiodarone is effective,provided that if an effective dose is assessed, dose adjustment isterminated; and e) if, at any time, it is determined that no dose ofbudiodarone equal to or less than 800 mg twice a day is effective forsaid qualified patient, determining that said qualified patient shouldbe disqualified from budiodarone therapy and terminating budiodaronetherapy for said disqualified patient.
 38. A method to determine whethera patient suffering from paroxysmal or persistent atrial fibrillation(AFib) and qualified for treatment with budiodarone therapy isresponsive to said budiodarone therapy or should be disqualified fromsaid budiodarone therapy, the method comprising: a) administering tosaid qualified patient a first dose of budiodarone of at least 600 mgtwice a day, wherein said qualified patient was qualified forbudiodarone therapy based on experiencing, over a qualification periodin which said qualified patient did not receive budiodarone therapy, oneor more of: a baseline number of episodes of long duration AFibsatisfying a threshold number of episodes of long duration AFib, or abaseline AFib burden of the patient satisfying a threshold AFib burden;b) monitoring heart rhythm data of said qualified patient beingadministered said first dose of budiodarone, wherein, at least about 3days after initiation of administration of said first dose, saidmonitored heart rhythm data is evaluated for one or more of: a number ofepisodes of long duration AFib, a length of episodes of long durationAFib, or an extent of AFib burden; c) assessing if the first dose ofbudiodarone is effective in treating AFib, wherein said first dose ofbudiodarone is assessed as effective if said first dose reduces, forsaid qualified patient and relative to baseline data collected duringsaid qualification period, one or more of: the number of episodes oflong duration AFib; the length of episodes of long duration AFib; or theAFib burden; d) if said first dose is assessed as not effective,adjusting said first dose of budiodarone one or more times, providedthat said adjusted dose does not exceed 800 mg twice a day, andassessing whether said adjusted dose of budiodarone is effective,provided that if an effective dose is assessed, dose adjustment isterminated; and e) if, at any time, it is determined that no dose ofbudiodarone equal to or less than 800 mg twice a day is effective forsaid qualified patient, determining that said qualified patient shouldbe disqualified from budiodarone therapy and terminating budiodaronetherapy for said disqualified patient.